Aryl and heteroaryl substituted fused pyrrole anti-inflammatory agents

ABSTRACT

The present invention comprises a new class of novel aryl and heteroaryl substituted fused pyrrole compounds useful for the prophylaxis and treatment of diseases or conditions, such as TNF-α, IL-1β , IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and treatment of inflammation and other maladies, such as pain and diabetes, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of compounds of the invention. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

[0001] This application is a division of application Ser. No.09/644,102, filed Aug. 23, 2000, which is a division of application Ser.No. 09/269,600, filed Jun. 8, 1999, which is a 35 USC 371 filing ofInternational Application No. PCT/US97/21344, filed Nov. 18, 1997, whichclaims the benefit of U.S. Provisional Application Serial No.60/031,207, filed Nov. 19, 1996, which are, in their entirety, herebyincorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] The present invention comprises a new class of compounds usefulin treating diseases, such as TNF-α, IL-1β, IL-6 and/or IL-8 mediateddiseases and other maladies, such as pain and diabetes. In particular,the compounds of the invention are useful for the prophylaxis andtreatment of diseases or conditions involving inflammation. Thisinvention, in particular, relates to novel aryl and heteroarylsubstituted fused pyrrole compounds, compositions containing suchcompounds and methods of use of such compounds. The subject inventionalso relates to processes for making such compounds as well as tointermediates useful in such processes.

[0003] Interleukin-1 (IL-1) and Tumor Necrosis Factor alpha (TNF-α) areproinflammatory cytokines secreted by a variety of cells includingmonocytes and macrophages in response to many inflammatory stimuli (e.g.lipopolysaccharide—LPS) or external cellular stress (e.g. osmotic shock,peroxide). Elevated levels of TNF-α and/or IL-1 over basal levels havebeen implicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis; Pagets disease; osteoporosis; multiplemyeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic βcell destruction; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type I and type II diabetes;bone resorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNFα.

[0004] Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type Iand type II diabetes; bone resorption diseases; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; sepsis;septic shock; and toxic shock syndrome. Viruses sensitive to TNFαinhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.

[0005] TNFα and IL-1 appear to play a role in pancreatic β celldestruction and diabetes. Pancreatic β cells produce insulin which helpsmediate blood glucose homeostasis. Deterioration of pancreatic β cellsoften accompanies type I diabetes. Pancreatic β cell functionalabnormalities may occur in patients with type II diabetes. Type IIdiabetes is characterized by a functional resistance to insulin.Further, type II diabetes is also often accompanied by elevated levelsof plasma glucagon and increased rates of hepatic glucose production.Glucagon is a regulatory hormone that attenuates liver gluconeogenesisinhibition by insulin. Glucagon receptors have been found in the liver,kidney and adipose tissue. Thus glucagon antagonists are useful forattenuating plasma glucose levels (WO 97/16442, incorporated herein byreference in its entirety). By antagonizing the glucagon receptors, itis thought that insulin responsiveness in the liver will improve,thereby decreasing gluconeogenesis and lowering the rate of hepaticglucose production.

[0006] Several approaches have been taken to block the effects of TNF-a.One approach involves utilizing soluble receptors for TNF-a (e.g.,TNFR-55 or TNFR-75) which have demonstrated efficacy in animal models ofTNF-a mediated disease states (for a PEG dimer of TNFR-55 see EdwardsCHI Meeting Nov. 13-15 (1995) and rhu sTNFR:Fc p-75 see Moreland). Asecond approach to neutralizing TNF-a utilizing a monoclonal antibodyspecific to TNF-a, cA2, has demonstrated improvement in swollen jointcount in a Phase II human trial of rheumatoid arthritis (Feldmann et alImmunological Reviews p.195-223 (1995)).

[0007] The above approaches block the effects of TNF-a and IL-1 byeither protein sequesterazation or receptor antagonism, but anadditional approach to blockade is to intervene in the cellularproduction and secretion of IL-1 and/or TNF. There are numerous pointsfor intervention between the extracellular stimulus and the secretion ofIL-1 and TNF-a from the cell including interfering with transcriptionalprocesses, interfering with translational processes, blocking signaltransduction which may alter protein translation and/or transcription;and blocking release of the proteins from the cells. The most reliableeffect to document is upon applying a given stimulus to a cell in vitro(e.g. monocyte), a certain amount of TNF or IL-1 (note: quantitated byenzyme linked immunoabsorbent assay, ELISA) is secreted over basallevels in the culture medium. Evidence as to the nature of interventionbetween the extracellular stimulus and the secretion of IL-1 and TNF-afrom the cell can be provided by in vitro biochemical experiments, butit does not preclude the fact that the compounds may be intervening at ayet undetermined point on the pathway between extracellular stimulus andsecretion of protein. Pentoxifylline is an example of a compound that isbelieved to intervene at the transcriptional level of IL-1 proteinsynthesis. Evidence suggests that the anti-inflammatory glucocorticoidsblock at both the transcriptional and translational levels (Lee et alCirculatory Shock 44:97-103 (1995)) of inflammatory mediators.Chloroquine (CQ) and hydroxychloroquine (HCQ) accumulate in lysosomes ofmonocytes (Borne Handbook of Cardiovascular and Anti-Inflammatory Agentsp27-104 (1986)). CQ and HCQ inhibit cartilage cathepsin B and cartilagechondromucoprotease, and they may have membrane stabilizing effects onthe lysozomes.

[0008] Since TNF-a is upstream in the cytokine cascade of inflammationwherein elevated levels of TNF-a lead to elevated levels of othercytokines including IL-1, IL-6 and IL-8, inhibiting the production ofTNF-a may also reduce levels of other cytokines including but notlimited to IL-1, IL-6 or IL-8. IL-8 is implicated in exacerbating and/orcausing many disease states in which massive neutrophil infiltrationinto sites of inflammation or injury (e.g., ischemia) is mediated by thechemotactic nature of IL-8 including but not limited to the following:asthma, inflammatory bowel disease, psoriasis, adult respiratorydistress syndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels would lead to diminished neutrophil infiltration. Evidencehas been reported that suggests P-38 plays a role in TNF inducedtranscriptional activation of IL-6 production (see: Walter Fiers EMBOJournal 1996, vol. 15, p 1914-23) and of IL-8 production (Dinarello,Proc. Nat. Acad. Sci. 1995 Vol 92, 12230-4).

[0009] In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytesand chondrocytes to produce collagenase and neutral proteases whichleads to tissue destruction within the arthritic joints. In a model ofarthritis, collagen-induced arthritis (CIA) in rats and mice,intraarticular administration of TNF-a either prior to or after theinduction of CIA led to an accelerated onset of arthritis and a moresevere course of the disease (Brahn et al Lymphokine Cytokine Res.(11):253-256, (1992); and Cooper Clin. Exp. Immunol. 898:244-250,(1992)).

[0010] It has been reported that TNF-a plays a role in head trauma,stroke, and ischemia. For instance, in animal models of head trauma(rat), TNF-a levels increased in the contused hemisphere (Shohami et alJ. Cereb. Blood Flow Metab. 14:615-619 (1994)). In an model of ischemiawherein the middle cerebral artery was occluded in rats, the levels ofmRNA of TNF-a increased (Feurstein et al Neurosci. Lett. 164: 125-128(1993)). Administration of TNF-a into the rat cortex resulted insignificant PMN accumulation in capillaries and adherance in small bloodvessels. The TNF-a promotes the infiltration of other cytokines (IL-1b,IL-6), and also chemokines, which promote neutrophil infiltration intothe infarct area (Feurstein Stroke 25:1481-1488 (1994)).

[0011] TNF-a may play a role in promoting certain viral life cycles anddisease states associated with them. For instance, TNF-a secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al, J. Immunol. 142: 431 (1989)). Therole of TNF-a in the HIV associated states of cachexia and muscledegradation has been discussed (Lahdevirta et al The American J. Med.85:289 (1988)).

[0012] Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; antiviral therapy including thoseviruses sensitive to TNF-a inhibition—HIV-1, HIV-2, HIV-3; cachexia;Reiter's syndrome; type II diabetes; bone resorption diseases; ischemiareperfusion injury; atherosclerosis; brain trauma; multiple sclerosis;sepsis; septic shock; and toxic shock syndrome.

[0013] In rheumatoid arthritis models in animals, multipleintraarticular injections of IL-1 have lead to an acute and destructiveform of arthritis (Chandrasekhar et al Clinical Immunol Immunopathol.55:382-400 (1990)). In studies using cultured rheumatoid synovial cells,IL-1 is a more potent inducer of stromelysin than is TNF-a (FiresteinAm. J. Pathol. 140:1309-1314, (1992)). At sites of local injection,neutrophil, lymphocyte, and monocyte emigration occurs. The emigrationis attributed to the induction of chemokines (i.e. IL-8), and the upregulation of adhesion molecules (Dinarello Eur. Cytokine Netw.5:517-531 (1994)).

[0014] IL-1 does play a role in promoting certain viral life cycles.Cytokine-induced increase of HIV expression in a chronically infectedmacrophage line has been associated with the concomitant and selectiveincrease of IL-1 production (Folks et al J. Immunol. 136:40-49, (1986)).The role of IL-1 in cachexia has been discussed (Beutler et al J.Immunol. 135:3969-3971 (1985)). The role of IL-1 in muscle degenerationhas been discussed (Baracos et al N. Eng. J. Med. 308:553-558 (1983)).

[0015] IL-8 has been implicated in exacerbating and/or causing manydisease states in which massive neutrophil infiltration into sites ofinflammation or injury (e.g. ischemia) is mediated by the chemotacticnature of IL-8 including but not limited to the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 apparently also has the ability to activate neutrophils. Thus,reduction in IL-8 levels could lead to diminished neutrophilinfiltration.

[0016] Substituted imidazole and fused imidazole compounds have beendescribed for use in the treatment of cytokine mediated diseases byinhibition of proinflammatory cytokines, such as IL-1, IL-6, IL-8 andTNF. Substituted imidazoles for use in the treatment of cytokinemediated diseases have been described in WO 93/14081; WO 96/21452; andWO 96/21654 (each of which is incorporated herein by reference in itsentirety). Substituted imidazoles for use in the treatment ofinflammation has been described in U.S. Pat. No. 3,929,807 (which isincorporated herein by reference in its entirety). Substituted fusedimidazole compounds for use in the treatment of cytokine mediateddiseases have been described in WO 88/01169; WO 90/15534; WO 91/00092;WO 92/10190; WO 92/10498; WO 92/12154; and WO 95/35304 (each of which isincorporated herein by reference in its entirety).

[0017] Several classes of diamino substituted azaindole compounds havebeen reported to be useful in the treatment of a variety of diseasesincluding inflammation (U.S. Pat. No. 5,502,187, which is incorporatedherein by reference in its entirety). Several classes of substitutedindole and azaindole compounds are known to be useful as endothelinreceptor antagonists for treating hypertension, renal failure andcerebrovascular disease (WO 94/14434 and WO 95/33748, each of which isincorporated herein by reference in its entirety). A related class ofsubstituted indoles has been reported as useful in the treatment ofatherosclerosis (DE 2909779 A1, which is incorporated herein byreference in its entirety). Variously substituted 7-azaindoles have beenprepared and reported for use as anti-ulcer drugs (JP 06247966, which isincorporated herein by reference in its entirety).

[0018] The preparation of 3-(4-pyridyl)indole compounds has beenreported (U.S. Pat. No. 3,551,567; FR 1587692; DE 1795061; Ukr. Kim. Zh.(Russ. Ed.) (1982), 48(1), 76-9; Khim. Geterotsikl. Soedin. (1980), (7),959-64; each of which is incorporated herein by reference in itsentirety). The preparation of 2,3-diphenylindole derivatives has beenreported (U.S. Pat. No. 3,654,308; U.S. Pat. No. 3,565,912; and FR1505197; each of which is incorporated herein by reference in itsentirety).

BRIEF DESCRIPTION OF THE INVENTION

[0019] The present invention relates to selected anti-inflammatorycompounds, analogs and pharmaceutically acceptable salts and prodrugsthereof. The subject compounds are characterized as aryl and heteroarylsubstituted fused pyrrole compounds. The invention compoundsadvantageously treat inflammation related diseases. Therefore, thisinvention also encompasses pharmaceutical compositions and methods forprophylaxis and treatment of inflammation. The subject invention alsorelates to processes for making such compounds as well as tointermediates useful in such processes.

DETAILED DESCRIPTION OF THE INVENTION

[0020] In accordance with the present invention, there is provided ananti-inflammatory compound of the Formula:

[0021] or a pharmaceutically acceptable salt thereof, wherein

[0022] X₁ is N, CH or CR₁; X₂ is N, CH or CR₂; X₃ is N, CH or CR₃; andX₄ is N, CH or CR₄; provided that at least one of X₁, X₂, X₃ and X₄ is Nor CH, and that not more than two of X₁, X₂, X₃ and X₄ are N; whereinR₁, R₂, R₃ and R₄ are each independently —Z—Y;

[0023] preferably, X₁ is N; X₂ is CH or CR₂; X₃ is CH or CR₃; and X₄ isCH or CR₄; and more preferably, X₁ is N; X₂ is CR₂; X₃ is CH or CR₃; andX₄ is CH;

[0024] wherein R₂ is independently —Z—Y; and preferably, R₂ isindependently Y; and R₃ is independently —Z—Y; preferably, R₃ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; more preferably, R₃is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; even more preferably, R₃ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, methoxy,trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido orN,N-dimethylamido radicals; and most preferably, R₃ is halo ortrifluoromethyl radicals; and R₄ is independently —Z—Y; and preferably,R₄ is independently Y; or

[0025] alternatively, preferably, X₁ is N; X₂ is CH or CR₂; X₃ is CH orCR₃; and X₄ is N; and more preferably, X₁ is N; X₂ is CR₂; X₃ is CH orCR₃; and X₄ is N;

[0026] wherein R₂ is independently —Z—Y; and preferably, R₂ isindependently —Z—Y; and R₃ is independently —Z—Y; preferably, R₃ ishalo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; and most preferably,R₃ is halo, trifluoromethyl, phenyl, methyl, acetyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; or

[0027] alternatively, preferably, X₁ is N; X₂ is CH or CR₂; X₃ is N; andX₄ is CH or CR₄; and more preferably, X₁ is N; X₂ is CR₂; X₃ is N; andX₄ is CH or CR₄;

[0028] wherein R₂ is independently —Z—Y; and preferably, R₂ isindependently Y; and R₄ is independently —Z—Y; preferably, R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxyethyl, hydroxymethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; more preferably, R₄is halo, phenyl, trifluoromethyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, N,N-dimethylamido, amido, methylsulfonyl oraminosulfonyl radicals; or

[0029] alternatively, preferably, X₁ is N; X₂ is N; X₃ is CH or CR₃; andX₄ is CH or CR₄; and more preferably, X₁ is N; X₂ is N; X₃ is CR₃; andX₄ is CH or CR₄;

[0030] wherein R₃ is independently —Z—Y; and preferably, R₃ isindependently Y; and R₄ is independently —Z—Y; preferably, R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; and more preferably,R₄ is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl,methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido,methylsulfonyl or aminosulfonyl radicals; or

[0031] alternatively, preferably, X₁ is CH or CR₁; X₂ is CH or CR₂; X₃is N; and X₄ is N; and more preferably, X₁ is CH or CR₁; X₂ is CR₂; X₃is N; and X₄ is N;

[0032] wherein R₁ is independently —Z—Y; preferably, R₁ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; and more preferably,R₁ is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl,methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido,methylsulfonyl or aminosulfonyl radicals; and R₂ is independently —Z—Y;and preferably, R₂ is independently Y; or

[0033] alternatively, preferably, X₁ is CH or CR₁; X₂ is CH or CR₂; X₃is CH or CR₃; and X₄ is CH or CR₄, provided that at least one of X₁, X₂,X₃ and X₄ is CH; more preferably, X₁ is CH; X₂ is CH; X₃ is CH or CR₃;and X₄ is CH or CR₄; and even more preferably, X₁ is CH; X₂ is CH; X₃ isCR₃; and X₄ is CH or CR₄;

[0034] wherein R₁ is independently —Z—Y; and preferably, R₁ isindependently Y; and R₂ is independently —Z—Y; and preferably, R₂ isindependently Y; and R₃ is independently —Z—Y; and preferably, R₃ isindependently Y; and R₄ is independently —Z—Y; preferably, R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; and more preferably,R₄ is halo, phenyl, trifluoromethyl, methyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl,methoxycarbonyl, ethoxycarbonyl, N,N-dimethylamido, amido,methylsulfonyl or aminosulfonyl radicals; or

[0035] alternatively, more preferably, X₁ is CH; X₂ is CH or CR₂; X₃ isCH or CR₃; and X₄ is CH; and even more preferably, X₁ is CH; X₂ is CR₂;X₃ is CH or CR₃; and X₄ is CH;

[0036] wherein R₂ is independently —Z—Y; and preferably, R₂ isindependently Y; and R₃ is independently —Z—Y; preferably, R₃ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; and more preferably,R₃ is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl,methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido,methylsulfonyl or aminosulfonyl radicals; and

[0037] provided that (1) R₂ and R₄ are not both substituted orunsubstituted amino radicals; (2) the total number of aryl, heteroaryl,cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3; and (3) thecombined total number of aryl, heteroaryl, cycloalkyl and heterocyclylradicals in R₁, R₂, R₃ and R₄ is 0-4, preferably 0-3;

[0038] each Z is independently a (1) bond; (2) alkyl, alkenyl or alkynylradical optionally substituted by (a) 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano or halo, and (b) 1-2 radicals ofheterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicalsof amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl orhaloalkyl; (3) heterocyclyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; or (4) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, halo, alkyl or haloalkyl;

[0039] preferably, each Z is independently a (1) bond; (2) C₁-C₈ alkyl,C₂-C₈ alkenyl or C₂-C₈ alkynyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, or heterocyclyl,aryl or heteroaryl optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; (3) heterocyclyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; or (4) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoyl amino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals;

[0040] more preferably, each Z is independently a (1) bond; (2) C₁-C₈alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radical optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, or heterocyclyl, aryl orheteroaryl optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonyl amino, C₁-C₄ alkylsulfonylaamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; (3) heterocyclyl radical optionally substituted by 1-2radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl or C₁-C₄ haloalkylof 1-3 halo radicals; or (4) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals;

[0041] even more preferably, each Z is independently a (1) bond; (2)C₁-C₈ alkyl or C₂-C₈ alkenyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂haloalkyl of 1-3 halo radicals; (3) heterocyclyl radical optionallysubstituted by 1-2 radicals of amino, di-(C₁-C₄ alkyl)amino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄alkyl radicals; or (4) aryl or heteroaryl radical optionally substitutedby 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₂ haloalkyl of 1-3 halo radicals;

[0042] yet more preferably, each Z is independently a (1) bond; (2)C₁-C₄ alkyl or C₂-C₅ alkenyl radical optionally substituted by 1-3radicals of amino, di-(C₁-C₂ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonyl amino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, orheterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicalsof amino, C₁-C₄ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonyl amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; (3) heterocyclylradical optionally substituted by 1-2 radicals of amino, di-(C₁-C₂alkyl)amino, (C₁-C₄ alkoxy) carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio or C₁-C₄ alkyl radicals; or (4) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonyl amino, hydroxy, C₁-C₂alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethylradicals;

[0043] yet even more preferably, each Z is independently a (1) bond; (2)C₁-C₄ alkyl or C₂-C₅ alkenyl radical optionally substituted by 1-3radicals of amino, di-(C₁-C₂ alkyl) amino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, or aryl or heteroaryloptionally substituted by 1-2 radicals of amino, di-(C₁-C₂ alkyl) amino,acetamido, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; or (3)aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, di-(C₁-C₂ alkyl)amino, acetamido, (C₁-C₄ alkoxy)carbonyl amino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals;

[0044] still more preferably, each Z is independently a (1) bond; or (2)C₁-C₄ alkyl radical optionally substituted by 1-2 radicals of amino,di-(C₁-C₂ alkyl)amino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂alkoxy, C₁-C₂ alkyl thio, halo, or aryl or heteroaryl optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; still even morepreferably, each Z is independently a (1) bond; or (2) C₁-C₄ alkylradical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or haloradicals; and most preferably, each Z is a bond;

[0045] each Y is independently a hydrogen radical, provided Z is otherthan a bond; or halo, cyano, nitro, —C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁,—C(NR₅)—NR₅R₂₁, —OR₂₁, —O—C(O)—R₂₁, —O—C(O)—NR₅R₂₁,—O—C(O)—NR₂₂—S(O)₂—R₂₀, —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀, —S(O)₂—NR₅R₂₁,—S(O)₂—NR₂₂—C(O)—R₂₁, —S(O)₂—NR₂₂—C(O)—OR₂₀, —S(O)₂—NR₂₂—C(O)—NR₅R₂₁,—NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—C(O)—OR₂₀, —NR₂₂—C(O)—NR₅R₂₁,—NR₂₂—C(NR₅)—NR₅R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical;

[0046] preferably, each Y is independently a hydrogen radical, providedZ is other than a bond; or halo, —C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁,—C(NR₅)—NR₅R₂₁, —OR₂₁, —O—C(O)—R₂₁, —O—C(O)—NR₅R₂₁, —SR₂₁, —S(O)—R₂₀,—S(O)₂—R₂₀, —S(O)₂—NR₅R₂₁, —NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—C(O)—OR₂₀,—NR₂₂—C(O)—NR₅R₂₁, —NR₂₂—C(NR₅)—NR₅R₂₁, —NR₂₂—S(O)₂—R₂₀ or—NR₂₂—S(O)₂—NR₅R₂₁ radical;

[0047] more preferably, each Y is independently a hydrogen radical,provided Z is other than a bond; or halo, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —OR₂₁, —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀, —S(O)₂—NR₅R₂₁,—NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—C(O)—OR₂₀, —NR₂₂—C(O)—NR₅R₂₁,—NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical;

[0048] even more preferably, each Y is independently a hydrogen radical,provided Z is other than a bond; or halo, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —OR₂₁, —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀, —S(O)₂—NR₅R₂₁,—NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical;

[0049] yet even more preferably, each Y is independently a hydrogenradical, provided Z is other than a bond; or halo, —C(O)—R₂₀,—C(O)—NR₅R₂₁, —OR₂₁, —SR₂₁, —S(O)—R₂₀, —NR₅R₂₁, —NR₂₂—C(O)—R₂₁,—NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; and most preferably, eachY is independently a hydrogen radical, provided Z is other than a bond;or halo, —NR₅R₂₁, —NR₂₂—C(O)—R₂₁ or —NR₂₂—S(O)₂—R₂₀ radical;

[0050] wherein each R5 is independently (1) hydrogen radicals; (2)alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio,cyano or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicalsoptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and

[0051] preferably, each R₅ is independently (1) hydrogen radicals; (2)C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radicals optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano orhalo; or (3) aryl, heteroaryl, aryl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl,heterocyclyl, heterocyclyl-C₁-C₄-alkyl, C₃-C₈ cycloalkyl orC₃-C₈-cycloalkyl-C₁-C₄-alkyl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of1-3 halo radicals;

[0052] more preferably, each R₅ is independently (1) hydrogen radicals;(2) C₁-C₄ alkyl, C₂-C₅ alkenyl or C₂-C₅ alkynyl radicals optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or halo;or (3) aryl, heteroaryl, aryl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl,heterocyclyl, heterocyclyl-C₁-C₄-alkyl, C₃-C₈ cycloalkyl orC₃-C₈-cycloalkyl-C₁-C₄-alkyl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl) amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of1-3 halo radicals;

[0053] even more preferably, each R₅ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl, alkyl or C₂-C₅ alkenyl radicals optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio or halo; or (3) phenyl-C₁-C₂-alkyl,heteroaryl-C₁-C₂-alkyl, heterocyclyl-C₁-C₂-alkyl orC₃-C₆-cycloalkyl-C₁-C₂-alkyl radicals optionally substituted by 1-3radicals of amino, di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 halo radicals;

[0054] yet even more preferably, each R₅ is independently (1) hydrogenradical; (2) C₁-C₄ alkyl radical optionally substituted by 1-3 radicalsof amino, di-(C₁-C₂-alkyl)amino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthioor halo; or (3) phenyl-C₁-C₂-alkyl, heteroaryl-C₁-C₂-alkyl,heterocyclyl-C₁-C₂-alkyl or C₃-C₆-cycloalkyl-C₁-C₂-alkyl radicalsoptionally substituted by 1-3 radicals of amino, di-(C₁-C₂-alkyl)amino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, methoxy, methylthio, cyano,C₁-C₄ alkyl or trifluoromethyl radicals;

[0055] still more preferably, each R₅ is independently (1) hydrogenradical; (2) C₁-C₄ alkyl radical optionally substituted by 1-3 haloradicals; or (3) phenyl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl, radicalsoptionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy,methoxy, methylthio, methyl or trifluoromethyl radicals; still even morepreferably, each R₅ is independently hydrogen or C₁-C₄ alkyl radical;and most preferably, each R₅ is a hydrogen radical;

[0056] wherein each R₂₀ is independently (1) alkyl, alkenyl or alkynylradicals optionally substituted by 1-3 radicals of-CO₂R₂₃, amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl,cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, alkanoyl,alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl or haloalkyl; (2) heterocyclyl radicaloptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;or (3) aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy,alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl; preferably,each R₂₀ is independently (1) C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈alkynyl radicals optionally substituted by 1-3 radicals of —CO₂R₂₃,amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄alkyl)amino, aminocarbonylamino, C₁-C₄ alkyl sulfonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo or aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio,aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄alkoxy) carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonyl amino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals;or (3) aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, azido, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals;

[0057] more preferably, each R₂₀ is independently (1) C₁-C₈ alkyl, C₂-C₅alkenyl or C₂-C₅ alkynyl radicals optionally substituted by 1-3 radicalsof —CO₂R₂₃, amino, C₁-C₄ alkyl amino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C I-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkyl sulfonyl, cyano, halo, C₁-C₄alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (2) heterocyclyl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; or(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicalsof amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals;

[0058] even more preferably, each R₂₀ is independently (1) C₁-C₈ alkylor C₂-C₅ alkenyl radicals optionally substituted by 1-3 radicals of-CO2R₂₃, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,halo or aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio,aryl-C₁-C₄-alkylsulfonyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄alkoxy) carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 halo radicals; (2) heterocyclylradical optionally substituted by 1-2 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoyl amino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkylor C₁-C₂ haloalkyl of 1-3 halo radicals;

[0059] yet more preferably, each R₂₀ is independently (1) C₁-C₈ alkyl orC₂-C₅ alkenyl radicals optionally substituted by 1-3 radicals of—CO₂R₂₃, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl) amino, aminocarbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,halo or aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio,aryl-C₁-C₄-alkylsulfonyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄alkoxy) carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 halo radicals; (2) heterocyclylradical optionally substituted by 1-2 radicals of amino, di-(C₁-C₄alkyl)amino, (C₁-C₄ alkoxy) carbonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals of amino,di-(C₁-C₄ alkyl)amino, acetamido, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, azido, C₁-C₄ alkyl or trifluoromethyl radicals;

[0060] still more preferably, each R₂₀ is independently (1) C₁-C₈ alkylradicals optionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonyl amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonyl amino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals;

[0061] still even more preferably, each R₂₀ is independently (1) C₁-C₆alkyl radicals optionally substituted by 1-3 radicals of —CO₂R₂₃, amino,methylamino, dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl) amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; and

[0062] most preferably, each R₂₀ is independently (1) C₁-C₆ alkylradicals optionally substituted by 1-3 radicals of —CO₂R₂₃, amino,methylamino, dimethylamino, t-butoxy carbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted byt-butoxycarbonyl; or (3) aryl or heteroaryl radicals optionallysubstituted by 1-2 radicals of t-butoxy carbonyl, hydroxy, methoxy,halo, azido, methyl or trifluoromethyl radicals;

[0063] each R₂₁ is independently hydrogen radical or R₂₀;

[0064] each R22 is independently (1) hydrogen radical; (2) alkyl radicaloptionally substituted by a radical of heterocyclyl, aryl or heteroaryloptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo,alkyl or haloalkyl; or (3) heterocyclyl, aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo,alkyl or haloalkyl; and

[0065] preferably, each R₂₂ is independently (1) hydrogen radical; (2)C₁-C₄ alkyl radical optionally substituted by a radical of heterocyclyl,aryl or heteroaryl optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino (C₁-C₄alkoxy) carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkyl sulfonyl, cyano, halo,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; or (3)heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; more preferably, each R₂₂ is independently (1) hydrogenradical; or (2) C₁-C₄ alkyl radical optionally substituted by a radicalof phenyl or heteroaryl optionally substituted by 1-3 radicals of amino,di-(C₁-C₂ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 halo radicals; even morepreferably, each R₂₂ is independently hydrogen or C₁-C₄ alkyl radical;and most preferably, each R₂₂ is independently hydrogen or methylradical;

[0066] each R₂₃ is independently hydrogen or alkyl, or aryl, heteroaryl,aralkyl or heteroaralkyl optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and

[0067] preferably, each R₂₃ is independently hydrogen or C₁-C₄ alkyl, oraryl, heteroaryl, aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals;

[0068] more preferably, each R₂₃ is independently hydrogen or C₁-C₄alkyl, or phenyl, heteroaryl, phenyl-C₁-C₂-alkyl orheteroaryl-C₁-C₂-alkyl optionally substituted by 1-3 radicals of amino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₂ haloalkyl of 1-3 halo radicals;

[0069] even more preferably, each R₂₃ is independently hydrogen or C₁-C₄alkyl, or phenyl, heteroaryl, phenyl-C₁-C₂-alkyl orheteroaryl-C₁-C₂-alkyl optionally substituted by 1-3 radicals of amino,di-(C₁-C₂ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals;

[0070] yet more preferably, each R₂₃ is independently hydrogen or C₁-C₄alkyl, or phenyl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino, acetamido,(C₁-C₄ alkoxy)carbonyl amino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; still morepreferably, each R₂₃ is independently hydrogen or C₁-C₄ alkyl, orphenyl-C₁-C₂-alkyl optionally substituted by 1-2 radicals of hydroxy,C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; and most preferably, each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl radicals;

[0071] R₁₀ is a hydrogen, R₃₀, —C(O)—R₂₉, —C(O)—OR₃₀, —C(O)—NR₃₁R₃₂,—S(O)₂—R₃₀ or —S(O)₂—NR₃₁R₃₂ radical; preferably, R₁₀ is a hydrogen,R₃₀, —C(O)—R₂₉, —C(O)—NR₃₁R₃₂, —S(O)₂—R₃₀ or —S(O)₂—NR₃₁R₃₂ radical;more preferably, R₁₀ is a hydrogen, R₃₀, —C(O)—R₂₉ or —C(O)—NR₃₁R₃₂radical; and most preferably, R₁₀ is a hydrogen or methyl radical;

[0072] R₁₁ and R₁₂ are each independently an aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of R₃₀, halo, cyano, —C(O)—R₃₀,—C(O)—OR₂₉, —C(O)—NR₃₁R₃₂, —C(NR₃₁)—NR₃₁R₃₂, —OR₂₉, —O—C(O)—R₂₉,—O—C(O)—NR₃₁R₃₂, —O—C(O)—NR₃₃—S(O)₂—R₃₀, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀,—S(O)₂—NR₃₁R₃₂, —S(O)₂—NR₃₃—C(O)—R₃₀, —S(O)₂—NR₃₃—C(O)—OR₃₀,—S(O)₂—NR₃₃—C(O)—NR₃₁R₃₂, —NR₃₁R₃₂, —NR₃₃—C(O)—R₂₉, —NR₃₃—C(O)—OR₃₀,—NR₃₃—C(O)—NR₃₁R₃₂, —NR₃₃—C(NR₃₁)—NR₃₁R₃₂, —NR₃₃—S(O)₂—R₃₀ or—NR₃₃—S(O)₂—NR₃₁R₃₂ radicals;

[0073] preferably, R₁₁ and R₁₂ are each independently an aryl orheteroaryl radical optionally substituted by 1-2 radicals of R₃₀, halo,cyano radicals, —C(O)—R₃₀, —C(O)—OR₂₉, —C(O)—NR₃₁R₃₂, —C(NR₃₁)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂,—NR₃₃—C(O)—R₂₉ or —NR₃₃—C(O)—OR₃₀ radicals;

[0074] more preferably, R₁₁ and R₁₂ are each independently an aryl orheteroaryl radical optionally substituted by 1-2 radicals of R₃₀, halo,cyano, —C(O)—R₃₀, —C(O)—OR₂₉, —C(O)—NR₃₁R₃₂, —C(NR₃₁)—NR₃₁R₃₂, —OR₂₉,—SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉radicals;

[0075] even more preferably, R₁₁ and R₁₂ are each independently an arylor heteroaryl radical optionally substituted by 1-2 radicals of R₃₀,halo, cyano, —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀,—S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;

[0076] yet more preferably, R₁₁ is a heteroaryl radical optionallysubstituted by 1-2 radicals of R₃₀, halo, cyano, —C(O)—NR₃₁R₃₂, —OR₂₉,—SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an aryl radicaloptionally substituted by 1-2 radicals of R₃₀, halo, cyano,—C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂,—NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;

[0077] still more preferably, R₁₁ is a heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R₁₂ is anaryl radical optionally substituted by 1-2 radicals of amino,dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio,methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethylradicals;

[0078] still even more preferably, R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals; and

[0079] most preferably, R₁₁ is a 4-pyridyl radical optionallysubstituted by a radical of amino, dimethylamino, acetamido, hydroxy,halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R₁₂ is anunsubstituted phenyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals;and

[0080] provided that the total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1; andprovided that when each of X₁, X₂, X₃ and X₄ represent carbon atoms,then R₁₁ is a substituted aryl radical and R₁₂ is heteroaryl radical, orR₁₁ is a heteroaryl radical and R₁₂ is a substituted aryl radical;

[0081] wherein each R₃₀ is independently (1) alkyl, alkenyl or alkynylradicals optionally substituted by 1-3 radicals of —NR₃₁R₃₁, —CO₂R₂₃,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo oraralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroarylradicals optionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoyl amino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo,alkyl or haloalkyl; (2) heterocyclyl radical optionally substituted by1-3 radicals of amino, alkyl amino, dialkylamino, alkanoyl amino,alkoxycarbonyl amino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, hydroxy,alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;

[0082] preferably, each R₃₀ is independently (1) C₁-C₄ alkyl, C₂-C₄alkenyl or C₂-C₄ alkynyl radicals optionally substituted by 1-3 radicalsof —NR₃₁R₃₁, —CO₂R₂₃, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, heterocyclyl, aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (2) heterocyclylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonyl amino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₄ haloalkyl of 1-3 halo radicals;

[0083] more preferably, each R₃₀ is independently (1) C₁-C₄ alkylradical optionally substituted by 1-3 radicals of (a) —NR₃₁R₃₁; (b)C₁-C₄ alkoxy-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyloptionally substituted by 1-3 radicals of amino, alkylamino,di-(C₁-C₄-alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkyl sulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl; or (c) hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, or phenyl-C₁-C₄-alkoxy, phenyl-C₁-C₄-alkylthio,heterocyclyl, phenyl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; (2) C₁-C₄ haloalkyl of 1-3 halo radical; or (3) aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, C₁-C₄ alkyl or trifluoromethyl radicals;

[0084] even more preferably, each R₃₀ is independently (1) C₁-C₄ alkylradical optionally substituted by (a) amino, C₁-C₄ alkylamino ordi-(C₁-C₄-alkyl)amino radicals; or (b) hydroxy, C₁-C₄ alkoxy,heterocyclyl, phenyl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; (2)C₁-C₂ haloalkyl of 1-3 halo radical; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals;

[0085] yet more preferably, each R₃₀ is independently (1) C₁-C₄ alkylradical optionally substituted by a phenyl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,acetamido, hydroxy, C₁-C₂ alkoxy, halo, C₁-C₄ alkyl or trifluoromethylradicals; (2) trifluoromethyl radical; or (3) aryl or heteroarylradicals optionally substituted by 1-3 radicals of amino, di-(C₁-C₂alkyl)amino, acetamido, hydroxy, C₁-C₂ alkoxy, halo, C₁-C₄ alkyl ortrifluoromethyl radicals;

[0086] still more preferably, each R₃₀ is independently (1) C₁-C₄ alkylradical optionally substituted by a phenyl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;(2) trifluoromethyl radical; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and most preferably, R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by a phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethylradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy,methyl or trifluoromethyl radicals;

[0087] each R₂₉ is independently hydrogen radical or R₃₀; andpreferably, R₂₉ is an aryl or heteroaryl radicals optionally substitutedby 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo,methoxy, methyl or trifluoromethyl radicals;

[0088] each R₃₁ is independently (1) hydrogen radicals; (2) alkylradical optionally substituted by an cycloalkyl, aryl, heterocyclyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl orhaloalkyl; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl radicaloptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, eachR₃₁ is independently (1) hydrogen radicals; (2) C₁-C₄ alkyl radicaloptionally substituted by an C₃-C₈ cycloalkyl, aryl, heterocyclyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoyl amino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) aryl, heteroaryl, heterocyclyl or C₃-C₈ cycloalkylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylaamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals;

[0089] more preferably, each R₃₁ is independently (1) hydrogen radicals;or (2) C₁-C₄ alkyl radical optionally substituted by an phenyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,C₁-C₄ alkyl or trifluoromethyl radicals; even more preferably, each R₃₁is independently hydrogen or C₁-C₄ alkyl radicals; and most preferably,R₃₁ is independently hydrogen, methyl or ethyl radicals;

[0090] each R₃₂ is independently (1) hydrogen radicals; (2) alkylradical optionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl,heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl;

[0091] preferably, each R₃₂ is independently (1) hydrogen radicals; (2)C₁-C₄ alkyl radical optionally substituted by an C₃-C₈ cycloalkyl, aryl,heterocyclyl or heteroaryl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoyl amino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl orC₃-C₈ cycloalkyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3halo radicals;

[0092] more preferably, each R₃₂ is independently (1) hydrogen radicals;(2) C₁-C₄ alkyl radical optionally substituted by an C₃-C₆ cycloalkyl,aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoyl amino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl orC₃-C₆ cycloalkyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3halo radicals;

[0093] even more preferably, each R₃₂ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl radical optionally substituted by phenyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkyl ortrifluoromethyl radicals; or (3) phenyl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkyl or trifluoromethyl radicals;

[0094] yet more preferably, each R₃₂ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl radical or C₁-C₂ alkyl radical substituted byphenyl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, di-(C₁-C₂ alkyl)amino, acetamido, hydroxy, C₁-C₂ alkoxy, C₁-C₄alkyl or trifluoromethyl radicals; or (3) phenyl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,acetamido, hydroxy, C₁-C₂ alkoxy, C₁-C₄ alkyl or trifluoromethylradicals;

[0095] still more preferably, each R₃₂ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl radical or C₁-C₂ alkyl radical substituted byphenyl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals; or (3) phenyl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy,methoxy, methyl or trifluoromethyl radicals; and

[0096] most preferably, each R₃₂ is independently (1) hydrogen or C₁-C₄alkyl radical; or (2) phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,methoxy, methyl or trifluoromethyl radicals; and

[0097] each R₃₃ is independently (1) hydrogen radical; or (2) alkylradical optionally substituted by a radical of heterocyclyl, aryl orheteroaryl optionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, eachR₃₃ is independently (1) hydrogen radical; or (2) C₁-C₄ alkyl radicaloptionally substituted by a radical of heterocyclyl, aryl or heteroaryloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; more preferably,each R₃₃ is independently hydrogen or C₁-C₄ alkyl radical; and mostpreferably, each R₃₃ is independently hydrogen or methyl radical.

[0098] Compounds of interest include the following:

[0099] 3-(4-pyridyl)-2-(4-fluorophenyl)indole;

[0100] 3-(4-fluorophenyl)-2-(4-pyridyl)indole;

[0101] 6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0102] 6-amino-3-(4-fluorophenyl)-2-(4-pyridyl)-7-aza-indole;

[0103]6-(4′-t-butoxycarbonylamino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0104]6-(4′-amino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0105] 6-(5′-ureido-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0106]6-(5′-ureido-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0107] 6-(6′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0108]6-(6′-amino-1′-oxo-2′-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0109] 6-(5′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0110]6-(5′-amino-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0111] 6-(3′-(4-iodophenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0112]6-(3′-(4-iodophenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0113]6-(3′-methyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0114]6-(3′-methyl-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0115] 6-(4′,4′-dimethyl-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0116]6-(4′,4′-dimethyl-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0117]6-(5′-t-butoxycarbonylamino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0118]6-(5′-amino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0119]6-(6′-t-butoxycarbonylamino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0120]6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0121] 6-(3′-cyclohexyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0122]6-(3′-cyclohexyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0123] 6-(4′-t-butoxycarbonyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0124]6-(4′-carboxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0125] 6-(3′-O-t-butoxy-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0126]6-(3′-hydroxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0127] 6-(3′-phenyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0128]6-(3′-phenyl-1′-oxo-2′-D,L-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0129] 6-(3′-(4-t-butoxyphenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0130]6-(3′-(4-hydroxyphenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0131]6-(3′-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0132]6-(3′-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0133]6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0134]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0135]6-(methylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0136]6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0137]6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0138]6-(phenylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0139]6-(2′-N-phthaloyl-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0140]6-(3′-N-phthaloyl-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0141] 3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole;

[0142]6-(2′-N-t-butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0143]6-(2′-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0144]6-(2S′-dimethylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0145]6-(2′-dimethylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0146]6-(2′-N-methyl-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0147]6-(2′-N-methyl-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0148]6-(4′-N-t-butoxycarbonylisonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0149]6-(4′-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0150] 6-(4′-methylsulfoxo-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0151]6-(4′-methylsulfoxo-1′-oxo-2′S-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0152] 6-(3′-(3-pyridyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0153]6-(3′-(3-pyridyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0154]6-(N,N-Di-t-butoxycarbonyl-L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0155]6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0156] 6-(N-t-butoxycarbonyl-3(S)1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0157] 6-(3(S) 1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxoamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0158] 6-(2′-phenyl-1′-oxo-2′R-N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0159]6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0160] 6-(2′-phenyl-1′-oxo-2′S-N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0161]6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0162] 6-(2′-phenyl-1′-oxo-2′R-N-t-butoxycarbonyl-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0163]6-(2′-phenyl-1′-oxo-2′R-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0164]6-(1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0165]6-(1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0166] 6-(3′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0167]6-(3′-phenyl-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0168] 6-(1′-oxo-2′S-t-butoxycarbonyl-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0169]6-(1′-oxo-2′S-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0170] 6-(1′-oxo-2′S-t-butoxycarbonyl-N-methyl-4-methyl-2-aminopentyl-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0171]6-(1′-oxo-2′S-N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluoropentyl)-7-aza-indole;

[0172]6-(1′-oxo-2′R-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0173]6-(1′-oxo-2′R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0174] 6-(3′-(2-thienyl)-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0175]6-(3′-(2-thienyl)-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0176] 6-(3′-(4-azidophenyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0177]6-(3′-(4-azidophenyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0178] 6-(3′-(3-benzothienyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0179]6-(3′-(3-benzothienyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0180] 6-(4′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0181]6-(4′-phenyl-1′-oxo-2′-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0182] 6-(4′-phenyl-1′-oxo-2′-(D)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0183]6-(4′-phenyl-1′-oxo-2′-(D)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0184]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole;

[0185]6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0186] 6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0187]6-(3′-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0188]6-(2′(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0189]6-(2′(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0190] 6-Amino-5-chloro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0191] 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0192] 6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0193]6-(di-isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0194]6-(2′,2′-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0195]6-(2′-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0196]6-(2′-thienylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0197]6-(3′,3′di-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0198] 6-(ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0199]6-(3′-phenyl-1′-oxo-2′-(R,S)-methylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0200]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;

[0201]6-(3′,3′-dimethyl-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0202]6-(ethoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;

[0203]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;

[0204]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole;and

[0205]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-cyclohexylmethyl-7-aza-indole.

[0206] As utilized herein, the following terms shall have the followingmeanings:

[0207] “Alkyl”, alone or in combination, means a straight-chain orbranched-chain alkyl radical containing preferably 1-15 carbon atoms(C₁-C₁₅), more preferably 1-8 carbon atoms (C₁-C₈), even more preferably1-6 carbon atoms (C₁-C₆), yet more preferably 1-4 carbon atoms (C₁-C₄),still more preferably 1-3 carbon atoms (C₁-C₃), and most preferably 1-2carbon atoms (C₁-C₂). Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,iso-amyl, hexyl, octyl and the like.

[0208] “Hydroxyalkyl”, alone or in combination, means an alkyl radicalas defined above wherein at least one hydrogen radical is replaced witha hydroxyl radical, preferably 1-3 hydrogen radicals are replaced byhydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced byhydroxyl radicals, and most such radicals include hydroxymethyl, 1-,2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl,1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.

[0209] “Alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds,preferably 1-2 double bonds and more preferably one double bond, andcontaining preferably 2-15 carbon atoms (C₂-C₁₅), more preferably 2-8carbon atoms (C₂-C₈), even more preferably 2-6 carbon atoms (C₂-C₆), yetmore preferably 2-4 carbon atoms (C₂-C₄), and still more preferably 2-3carbon atoms (C₂-C₃). Examples of such alkenyl radicals include ethenyl,propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

[0210] “Alkynyl”, alone or in combination, means a straight-chain orbranched chain hydrocarbon radical having one or more triple bonds,preferably 1-2 triple bonds and more preferably one triple bond, andcontaining preferably 2-15 carbon atoms (C₂-C₁₅), more preferably 2-8carbon atoms (C₂-C₈), even more preferably 2-6 carbon atoms (C₂-C₆), yetmore preferably 2-4 carbon atoms (C₂-C₄), and still more preferably 2-3carbon atoms (C₂-C₃). Examples of such alkynyl radicals include ethynyl,propynyl (propargyl), butynyl and the like.

[0211] “Alkoxy”, alone or in combination, means a radical of the type“R—O—” wherein “R” is an alkyl radical as defined above and “O” is anoxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like.

[0212] “Alkoxycarbonyl”, alone or in combination, means a radical of thetype “R—O—C(O)—” wherein “R—O-” is an alkoxy radical as defined aboveand “C(O)” is a carbonyl radical.

[0213] “Alkoxycarbonylamino”, alone or in combination means a radical ofthe type “R—O—C(O)—NH—” wherein “R—O—C(O)” is an alkoxycarbonyl radicalas defined above, wherein the amino radical may optionally besubstituted, such as with alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl and the like.

[0214] “Alkylthio”, alone or in combination, means a radical of the type“R—S—” wherein “R” is an alkyl radical as defined above and “S” is asulfur atom. Examples of such alkylthio radicals include methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio,sec-butylthio, tert-butylthio and the like.

[0215] “Alkylsulfinyl”, alone or in combination, means a radical of thetype “R—S(O)—” wherein “R” is an alkyl radical as defined above and“S(O)” is a mono-oxygenated sulfur atom. Examples of such alkylsulfinylradicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl,sec-butylsulfinyl, tert-butylsulfinyl and the like.

[0216] “Alkylsulfonyl”, alone or in combination, means a radical of thetype “R—S(O)₂—” wherein “R” is an alkyl radical as defined above and“S(O)₂” is a di-oxygenated sulfur atom. Examples of such alkylsulfonylradicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl and the like.

[0217] “Alkylsulfonylamino”, alone or in combination, means a radical ofthe type “R—S(O)₂—NH—” wherein “R—S(O)₂—” is an alkylsulfonyl radical asdefined above, wherein the amino radical may optionally be substituted,such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and thelike.

[0218] “Aryl”, alone or in combination, means a phenyl or naphthylradical which is optionally substituted with one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro,cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino,alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido,aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and thelike. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-CF₃-phenyl,4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl,3-acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl,2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and thelike.

[0219] “Aralkyl”, alone or in combination, means an alkyl radical asdefined above in which at least one hydrogen atom, preferably 1-2, isreplaced by an aryl radical as defined above, such as benzyl, 1-,2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl,diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and thelike.

[0220] “Aralkoxy”, alone or in combination, means an alkoxy radical asdefined above in which at least one hydrogen atom, preferably 1-2, isreplaced by an aryl radical as defined above, such as benzyloxy, 1-,2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy,methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy andthe like.

[0221] “Aralkoxycarbonyl”, alone or in combination, means a radical ofthe type “R—O—C(O)—” wherein “R—O—” is an aralkoxy radical as definedabove and “—C(O)—” is a carbonyl radical.

[0222] “Aryloxy”, alone or in combination, means a radical of the type“R—O—” wherein “R” is an aryl radical as defined above.

[0223] “Alkanoyl”, alone or in combination, means a radical of the type“R—C(O)—” wherein “R” is an alkyl radical as defined above and “—C(O)—”is a carbonyl radical. Examples of such alkanoyl radicals includeacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl,4-methylvaleryl, and the like.

[0224] “Alkanoylamino”, alone or in combination, means a radical of thetype “R—C(O)—NH—” wherein “R—C(O)—” is an alkanoyl radical as definedabove, wherein the amino radical may optionally be substituted, such aswith alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.

[0225] “Aminocarbonyl”, alone or in combination, means an aminosubstituted carbonyl (carbamoyl) radical, wherein the amino radical mayoptionally be mono- or di-substituted, such as with alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl,aralkoxycarbonyl and the like. “Aminocarbonylamino”, alone or incombination, means an amino substituted carbonyl substituted on a secondamino (ureido) radical, wherein each amino radical may optionally bemono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and thelike.

[0226] “Aminoalkanoyl”, alone or in combination, means an alkanoylradical as defined above derived in which at least one, preferably 1-2,hydrogen atom is replaced by an amino radical, wherein each aminoradical may optionally be mono- or di-substituted, such as with alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl,aralkoxycarbonyl and the like.

[0227] “Benzo”, alone or in combination, means the divalent radicalC₆H₄═ derived from benzene.

[0228] “Bicyclic” as used herein is intended to include both fused ringsystems, such as naphthyl and β-carbolinyl, and substituted ringsystems, such as biphenyl, phenylpyridyl, naphthyl anddiphenylpiperazinyl.

[0229] “Cycloalkyl”, alone or in combination, means a saturated orpartially saturated, preferably one double bond, monocyclic or bicyclicalkyl radical, preferably monocyclic, containing preferably 3-10 carbonatoms (C₃-C₁₀), more preferably 3-8 carbon atoms (C₃-C₈), even morepreferably 3-6 carbon atoms (C₃-C₆), which is optionally be benzo fusedand which is optionally substituted as defined herein with respect tothe definition of aryl. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl,cycloheptyl, octahydronaphthyl, tetrahydronaphthyl,dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl and the like.

[0230] “Cycloalkylalkyl”, alone or in combination, means an alkylradical as defined above which is substituted by a cycloalkyl radical asdefined above. Examples of such cycloalkylalkyl radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl,tetrahydronaphthylpropyl, cyclohexylbutyl and the like.

[0231] “cycloalkylcarbonyl” means an acyl radical of the formulacycloalkyl—C(O)— in which the term “cycloalkyl” has the significancegive above, such as cyclopropylcarbonyl, cyclohexylcarbonyl,adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like.

[0232] “Heteroatoms” means nitrogen, oxygen and sulfur heteroatoms.

[0233] “Heterocyclyl”, alone or in combination, means a saturated orpartially unsaturated, preferably one double bond, monocyclic orbicyclic, preferably monocyclic, heterocycle radical containing at leastone, preferably 1 to 4, more preferably I to 3, even more preferably1-2, nitrogen, oxygen or sulfur atom ring member and having preferably3-8 ring members in each ring, more preferably 5-8 ring members in eachring and even more preferably 5-6 ring members in each ring.“Heterocyclyl” is intended to include sulfone and sulfoxide derivativesof sulfur ring members and N-oxides of tertiary nitrogen ring members,and carbocyclic fused, preferably 3-6 carbon atoms and more preferably5-6 carbon atoms, and benzo fused ring systems. “Heterocyclyl” radicalsmay optionally be substituted on at least one, preferably 1-4, morepreferably 1-3, even more preferably 1-2, carbon atoms by halogen,alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl,heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino,alkylsulfonylamino and the like, and/or on a secondary nitrogen atom byhydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl,heteroaralkyl, aryl or aralkyl radicals. More preferably,“heterocyclyl”, alone or in combination, is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals. Examples ofsuch heterocyclyl radicals include pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl,pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl,pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfonederivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl,2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl,ethylenedioxyphenyl and the like.

[0234] “Heterocyclylalkyl”, alone or in combination, means an alkylradical as defined above in which at least one hydrogen atom, preferably1-2, is replaced by a heterocyclyl radical as defined above, such aspyrrolidinylmethyl, tetrahydrothienylmethyl, piperidinylethyl and thelike.

[0235] “Heteroaryl”, alone or in combination, means a monocyclic orbicyclic, preferably monocyclic, aromatic heterocycle radical, having atleast one, preferably 1 to 4, more preferably 1 to 3, even morepreferably 1-2, nitrogen, oxygen or sulfur atom ring member and havingpreferably 5-6 ring members in each ring, which is optionally benzofused or saturated carbocyclic fused, preferably 3-4 carbon atoms(C₃-C₄) and which is optionally substituted as defined above withrespect to the definitions of aryl and heterocyclyl. More preferably,“heteroaryl”, alone or in combination, is a radical of a monocyclic orbicyclic aromatic heterocyclic ring system having 5-6 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused. Examples of such heteroaryl groups includeimidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl,pyridyl, 2-(1-piperidinyl)pyridyl, 2-(4-benzylpiperazin-1-yl)-1-pyridinyl, pyrazinyl, triazolyl, furyl, thienyl,oxazolyl, thiazolyl, indolyl, quinolinyl, I -oxido-2-quinolinyl,isoquinolinyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl,β-carbolinyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.

[0236] “Heteroaralkyl”, alone or in combination, means an alkyl radicalas defined above in which at least one hydrogen atom, preferably 1-2, isreplaced by a heteroaryl radical as defined above, such as3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl,2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.

[0237] “Halogen” and “halo”, alone or in combination, means fluoro,chloro, bromo or iodo radicals.

[0238] “Haloalkyl”, alone or in combination, means an alkyl radical asdefined above in which at least one hydrogen atom, preferably 1-3, isreplaced by a halogen radical, more preferably fluoro or chlororadicals. Examples of such haloalkyl radicals include1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and thelike.

[0239] “Leaving group” generally refers to groups readily displaceableby a nucleophile, such as an amine, a thiol or an alcohol nucleophile.Such leaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

[0240] “Protecting group” generally refers to groups well known in theart which are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also suitable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

[0241] Silyl protecting groups are silicon atoms optionally substitutedby one or more alkyl, aryl and aralkyl groups. Suitable silyl protectinggroups include, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

[0242] Protecting groups are removed under conditions which will notaffect the remaining portion of the molecule. These methods are wellknown in the art and include acid hydrolysis, hydrogenolysis and thelike. A preferred method involves removal of a protecting group, such asremoval of a benzyloxycarbonyl group by hydrogenolysis utilizingpalladium on carbon in a suitable solvent system such as an alcohol,acetic acid, and the like or mixtures thereof. A t-butoxycarbonylprotecting group can be removed utilizing an inorganic or organic acid,such as HCl or trifluoroacetic acid, in a suitable solvent system, suchas dioxane or methylene chloride. The resulting amino salt can readilybe neutralized to yield the free amine. Carboxy protecting group, suchas methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and thelike, can be removed under hydroylsis and hydrogenolysis conditions wellknown to those skilled in the art.

[0243] Procedures for preparing the compounds of this invention are setforth below. It should be noted that the general procedures are shown asit relates to preparation of compounds having unspecifiedstereochemistry. However, such procedures are generally applicable tothose compounds of a specific stereochemistry, e.g., where thestereochemistry about a group is (S) or (R). In addition, the compoundshaving one stereochemistry (e.g., (R)) can often be utilized to producethose having opposite stereochemistry (i.e., (S)) using well-knownmethods, for example, by inversion.

Preparation of Compounds of Formula I

[0244] The compounds of the present invention represented by Formula Iabove can be prepared utilizing the following general procedures asschematically shown in Schemes I and II.

[0245] The compounds of the present invention represented by Formula Iabove can be prepared utilizing the following general procedures asschematically shown in Schemes I and II.

[0246] Several types of indole and azaindole synthesis can be used toprepare the compounds of this invention which are included by reference(for reviews of indole synthesis see G. Gribble Recent Developments inIndole Ring Synthesis-Methodology and Applications in ContemporaryOrganic Synthesis p-145-172; R. Sundberg and P. V. Nguyen Five MemberedRing Systems: Pyrroles and Benzo Derivatives, Chapter 5, ComprehensiveHeterocyclic Chemistry) and the schemes shown below.

[0247] A general synthesis of indoles and azaindoles useful for thepreparation of the novel compounds of this invention is illustrated inScheme I whereby an appropriately substituted acetylene (II) is coupledwith an ortho iodoaniline (I) or a 1,2-iodoaminoheterocycle (forexample, 2-amino-3-iodopyridine) using a 15 palladium (0) mediatedcoupling under the conditions of Larock and coworkers(tetrabutylammonium chloride 1 eq., potassium acetate 5 eq., andtriphenylphosphine (5 mol %), Tet. Lett. 1993, 2823-2826) to afford amixture of regioisomeric indoles or azaindoles (III and IV) that can beseparated by chromatography. Preferably, when utilizing the generalsynthesis of Scheme I in the preparation of the novel compounds of thisinvention, R₁, R₂, R₃ and R₄ will not contain halogen substituted arylor heteroaryl and other radicals well known to those skilled in the artwhich have the potential of interfering with, competing with orinhibiting the ring formation reaction.

[0248] A second general synthesis of indoles and azaindoles useful forthe preparation of the novel compounds of this invention is illustratedin Scheme II whereby an appropriately substituted alpha-hydroxyketone(VI) or alpha-silyloxyketone (VIa) is coupled with an appropriatelysubstituted aniline or amino substituted heterocycle (V) (for example,2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3-amino-6-chloropyridazine, 3-phenyl-6-aminopyridazine, 4-amino pyridazine,3-methoxy-4-amino-6-chloropyridazine, 4-amino-2,6-dichloropyridine,4-amino-2-chloropyridine, 4-amino-5-cyano-2-methoxy-pyridine,4-amino-2-methyl pyridine, 4-amino-5-cyano-2-methoxypyridine,2-amino-4-methylpyridine, 2-amino-4,6-dimethylpyridine,2-amino-5-bromopyridine, 6-aminonicotinamide, 3-amino-2-chloro pyridine,5-amino-2-chloropyridine, 5-amino-2-methoxy pyridine,3-amino-2,6-dimethoxypyridine, 2,6-diamino pyridine, 2-aminopyrazine and2,4-diamino pyrimidine, which are commercially available) under acidcatalysis (in concentrated sulfuric acid at 190° C. see: Herbert et alJ. Chem. Soc. C 1969, p. 1505 or preferably under catalysis byp-toluenesulfonic acid in xylene with heat, see J. Szmuskovicz U.S. Pat.No. 3,565,912) to afford the regioisomeric indoles (III and IV) that canbe separated by chromatography. Preferably, when utilizing the generalsynthesis of Scheme II in the preparation of the novel compounds of thisinvention, R₁, R₂, R₃ and R₄ will not contain an amino substituted arylor heteroaryl and other radicals well known to those skilled in the artwhich have the potential of interfering with, competing with orinhibiting the ring formation reaction. The yields for the generalreaction of Scheme II are more favorable when the substituted aniline oramino substituted heterocycle (V) is electron rich.

[0249] Preferably, when R₁, R₂, R₃ or R₄ represent an electronwithdrawing group directly attached to the aromatic ring, the electronwithdrawing substituent should be introduced after the ring formation ofScheme II.

[0250] In a third general synthesis of indoles and azaindoles useful forthe preparation of the novel compounds of this invention is illustratedin Scheme III whereby the appropriate grignard reagent is added to thecyano functional group of a 2-amino-1-cyanoaryl or heteroaryl (forexample, 3-amino-4-cyanopyridine, 2-amino-5-nitrobenzonitrile,2-amino-6-fluorobenzonitrile

[0251] and 2-amino-5-chlorobenzonitrile, which are commerciallyavailable) system (VII) to afford the corresponding imine which uponhydrolysis affords the ketone (VIII). Alternatively, an orthonitrobenzonitrile (for example, 2-methyl-6-nitrobenzonitrile,5-chloro-2-nitrobenzonitrile, 4-cyano-3-nitrobenzotriflouride,4,5-dimethoxy-2-nitrobenzonitrile, 4-chloro-2-nitrobenzonitrile,6-nitro-o-anisonitrile and 6-bromo-2-cyano-4-nitroaniline, which arecommercially available) can be converted into a 2-aminobenzonitrile asdescribed by Jacini et al (Gazz. Chim. Ital. 1947, vol 77, 308).Acylation of the amino aryl or aminoheterocycle with the appropriateacid chloride (IX) (for example, benzoyl chloride,3,5-bis(trifluoromethyl)benzoyl chloride, 2-bromobenzoyl chloride,2-fluorobenzoyl chloride, pentafluorobenzoyl chloride,2,4-difluorobenzoyl chloride, 2,6-difluorobenzoyl chloride,2,6-dichlorobenzoyl chloride, o-toluoyl chloride, m-anisoyl chloride,3,4,5-trimethoxybenzoyl chloride, 4-biphenylcarbonyl chloride,4-tert-butylbenzoyl chloride, 4-n-butylbenzoyl chloride, 4-cyanobenzoylchloride, 2-naphthoyl chloride, 2,5-difluorobenzoyl chloride,5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride, 2,3-dichlorobenzoylchloride, 1-naphthoyl chloride, 2-ethoxy-1-naphthoyl chloride and2-naphthoyl chloride, which are commercially available) as shown inScheme III affords the fused bicycle (III) after treatment with titanium(0) as described in the literature (Furstner et al Tet. Lett. 1991,6695-6696). Such substituted benzoyl chlorides can be prepared from thecorresponding commercially available benzoic acids by treatment withoxalyl chloride or thionyl chloride (Tet. Lett. 1993, 3543-3546; andJulia et al J. Chem. Soc. Perkin Trans. I1991, Vol 5, 1101-1105,respectively).

[0252] A general preparation of acetylenes for use in coupling in SchemeI is illustrated in Scheme IV. The appropriate aryl or heteroarylaldehyde (XI) is reacted with diphenyl phosphite (XII) to afford thecarbinol derivative (XIII) which is subsequently converted to the chloroderivative (XIV) by treatment with phosphorous oxychloride. Treatment ofthe chloromethanephosphonate with two equivalents of potassiumt-butoxide followed by addition of the appropriate aldehyde (XV) affordsthe desired acetylene derivative (II) for use in Scheme I.

[0253] For purposes of illustration, examples of commercially availablearyl aldehydes (XI) include 3-phenoxybenzaldehyde,6-bromoveratraldehyde, 2-bromo benzaldehyde, 2-fluorobenzaldehyde,4-fluoro benzaldehyde, 2-chlorobenzaldehyde, 2,4-dichloro benzaldehyde,2-chloro-6-fluorobenzaldehyde, o-anisaldehyde,2,3-dimethoxybenzaldehyde, 3-cyano benzaldehyde,3-fluoro-p-anisaldehyde, 3-(3,4-dichlorophenoxy)benzaldehyde,3-(3-(trifluoromethyl) phenoxy)benzaldehyde, 3-(4-methoxyphenoxy)benzaldehyde, 3-methyl-p-anisaldehyde,4,4′-ethylbiphenyl-4-carboxaldehyde,2-chloro-4-dimethylaminobenzaldehyde, 2,4,5-triethoxybenzaldehyde,1-naphthaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1naphthaldehyde, 4-dimethylamino-1-naphthaldehyde,4-methyl-1-naphthaldehyde, 2-benzyloxy-1-naphthaldehyde,2-(2,4-dichlorobenzyloxy)-1-naphthaldehyde, 2-naphthaldehyde,1-bromo-2-naphthaldehyde, 6-methoxy-2-naphthaldehyde and7-methyl-2-naphthaldehyde.

[0254] For purposes of illustration, examples of commercially availableheteroaryl aldehydes (XI) include 2,6-diphenyl-4-pyridinecarboxaldehyde,quinoline-3-carboxaldehyde, 2-chloro-3-quinolinecarboxaldehyde,2-chloro-6-methoxy-3-quinolinecarboxaldehyde, 2-imidazolecarboxaldehyde,N-1-benzyl-2-imidazole carboxaldehyde,2-methyl-3-imidazolecarboxaldehyde, 3-imidazolecarboxaldehyde,2-ethyl-4-methyl-3-imidazolecarboxaldehyde, 4-methyl-5-imidazolecarboxaldehyde and 2-phenyl-4-imidazolecarboxaldehyde.

[0255] Further, commercially available heteroaryrl carboxylic acids orderivatives thereof can be converted to heteroaryl aldehydes by standardsynthetic transformations well known to those skilled in the art. Forexample, heteroarylester can be reduced to the aldehyde by treatmentwith diisobutylaluminum hydride. For purposes of illustration,commercially available heteroaryl-carboxylic acids or derivativesthereof that can be converted into heteroaryl aldehydes (XI) includemethyl 2-chloro-6-methyl-4-pyrimidinecarboxylate; 4-carboxypyrimidine;methyl 2,6-dimethylamino-4-pyrimidine carboxylate; and methyl4,6-diphenyl-2-pyrimidine carboxylate.

[0256] Alternatively, heteroaryl-halides can be converted intoheteroaryl aldehydes (XI) by lithium-halogen exchange and quenching ofthe anion with dimethylformamide. For purposes of illustration,commercially available heteroarylhalides that can be converted intoheteroaryl aldehydes (XI) include 6-chloro-2,4-dimethoxypyrimidine;4-chloro-2-methylthio pyrimidine; 2-amino-4-chloro-6-methylpyrimidine;4-chloro-2-phenylquinazoline; 4-chloro-2-methylquinoline;4-chloro-2-methylquinoline; 4-chloro-7-(trifluoromethyl) quinoline;4-chloro-6-methoxyquinoline; 4-chloro-2-picoline;2,5-dimethyl-4-bromopyridine; 2-ethoxy-4-bromopyridine;3-amino-4-chloroquinoline; and 3-amino-4-chloropyridine (note: the aminogroup of the substituted heteroaryl halide derivatives would first besuitably protected).

[0257] The alphahydroxyketone (VIa) or alphasilyloxyketone (VIb) ofScheme II can be prepared, for example when R₁₁ is 4-pyridyl or4-quinolinyl, by generating the anion of the protected silyl ether (XVI)and reacting it with the N-methyl-N-methoxyamide (XVII) as shown inScheme Va (Gallagher et al Biorg. Med. Chem. Lett. 1995, 1171-1176). TheN-methyl-N-methoxyamide (XVII) can be obtained through reaction ofR₁₂—C(O)Cl (for example, 3,5-bis(trifluoromethyl)benzoyl chloride;2-bromobenzoyl chloride; 2-fluorobenzoyl chloride; pentafluorobenzoylchloride; 2,4-difluorobenzoyl chloride; 2,6-difluoro benzoyl chloride;2,6-dichlorobenzoyl chloride; o-toluoyl chloride; m-anisoyl chloride;3,4,5-trimethoxy benzoyl chloride; 4-biphenylcarbonyl chloride;4-tert-butyl benzoyl chloride; 4-n-butylbenzoyl chloride; 4-cyanobenzoyl chloride; 2-naphthoyl chloride; 2,5-difluoro benzoyl chloride;5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride; 2,3-dichlorobenzoylchloride; 1-naphthoyl chloride; 2-ethoxy-1-naphthoyl chloride; and2-naphthoyl chloride, which are commercially available) withN,O-dimethylhydroxylamine in the presence of triethylamine. Such acidchlorides can be prepared from the corresponding R₁₂—C(O)OH by treatmentwith oxalyl chloride or thionyl chloride (Tet. Lett. 1993, 3543-3546 andJulia et al J. Chem. Soc. Perkin Trans. I 1991, Vol 5, 1101-1105,respectively).

[0258] Alternatively, the dimethylketal XX, prepared according to SchemeVb, can be used in the process of Scheme II in place of thealphahydroxyketone (VIa) and alphasilyloxyketone (VIb). Thedimethylketal XX can be prepared by reacting the anion of thedimethoxyacetal XIX with the aldehyde XV. The dimethoxyacetal XIX can bereadily prepared from the corresponding aldehyde XI (for example,2,6-diphenyl-4-pyridinecarboxaldehyde; quinoline-3-carboxaldehyde;2-chloro-3-quinoline carboxaldehyde; 2-chloro-6-methoxy-3-quinolinecarboxaldehyde; 2-imidazolecarboxaldehyde;N-1-benzyl-2-imidazolecarboxaldehyde; 2-methyl-3-imidazolecarboxaldehyde; 3-imidazolecarboxaldehyde;2-ethyl-4-methyl-3-imidazolecarboxaldehyde; 4-methyl-5-imidazolecarboxaldehyde; and 2-phenyl-4-imidazolecarboxaldehyde, which arecommercially available) using methods well know to those skilled in theart.

[0259] Alternatively, indoles or azaindoles (III) can be prepared(Scheme VI) by reacting 2-substituted indoles or azaindoles (XIX) (forexample, 2-(4-fluorophenyl) indole; 2-(2-naphthyl)indole; and2-(4-chlorophenyl) indole, which are commercially available) with R₁₁-L,where L is a leaving group such as chloro, bromo, iodo, and the likeradicals (for example, 4-chloropyridine, 4-chloroquinoline or4-chloropyrimidine, which are commercially available). The 2-substitutedindole or azaindole (XIX) can be treated with methyl magnesium bromidein ether followed by the addition of R₁₁-L and heated in a metal bomb at160° C. for 20 hours to afford the indole or azaindole (III) (U.S. Pat.No. 3,551,567).

[0260] The following is included to further illustrate syntheticprocedures useful in the preparation of the novel compounds of thisinvention. A specific example of a palladium mediated coupling asdescribed in Scheme I is illustrated in Scheme VII wherein1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) and 2-iodoaniline (2) affordsthe regioisomeric 2,3-disubstituted indoles (3) and (4) as a 1:4mixture, respectively. Compound (4) can be separated from compound (3)via flash chromatography.

[0261] Alternatively, substituted acetylenes and iodoanilines can becoupled via a palladium mediated process as described in Scheme I.Substituted 2-iodoanilines can either be purchased or prepared bystandard methods well known to those skilled in the art. For instance,monoiodination of a substituted aniline derivative would afford the2-iodoaniline derivative using a variety of iodination reagents, such asN-iodo succinimide. Substituted acetylenes can be obtained as describedin Scheme IV as illustrated in Scheme VIII for1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1). The adduct (6) ofdiphenylphosphite and 4-pyridinecarboxaldehyde (5) is treated withphosphorous oxychloride to afford the chloro derivative (7).Condensation and elimination to the alkyne (1) is effected by treatingthe chloro derivative (7) and 4-fluorobenzaldehyde (8) with 2.1equivalents of potassium t-butoxide.

[0262] Scheme IX illustrates the preparation of substituted indolesaccording to the method of Scheme III, a titanium oxide mediatedcoupling. The grignard of 4-bromopyridine (10) is prepared by lowtemperature treatment (−78° C.) with n-butyl lithium followed bytreatment with magnesium bromide etherate. A cooled solution of thegrignard of (10) is added to anthranilonitrile (9) at low temperature(−50° C.) followed by warming to room temperature. The resultant imine(11) is hydrolyzed by treatment with sulfuric acid to the anilinoketone(12). Acylation of the anilinoketone (12) with 4-fluorobenzoyl chloride(13) affords the ketoamide (14). The regiospecific synthesis of indole(3) is completed by treatment of the ketoamide (14) with titanium oxide.

[0263] Scheme X illustrates the preparation of indoles and azaindolesaccording to the method of Scheme II, acid mediated condensation of anaminoaryl or aminoheteroaryl and a substituted benzoin. Condensation of2,6-diaminopyridine (15) with1-(4-fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone (16) iseffected by treatment with an excess of p-toluenesulfonic acid in xyleneat high temperatures to afford the azaindoles (17) and (18) which can beseparated by flash chromatography.

[0264] Further functionalization of the 2,3-disubstituted indoles orazaindoles can be readily accomplished by reaction at an appropriatelypositioned group, such as an amino, carboxy, halo, substituted alkyl andthe like group, on the 2,3-disubstituted indoles or azaindoles. SchemeXI illustrates functionalizing a 6-amino derivative (17) of a2,3-disubstituted azaindole. Reaction of the 6-amino group of (17) withthe mixed anhydride of N-4-t-butoxycarbonylaminobutyric acid (20)affords the N-4-t-butoxycarbonylaminobutanoyl compound (21), which canbe readily converted into the aminobutanoyl compound (22) by exposure to90% trifluoroacetic acid and water for 1 hour. Similarly, theaminoalkylsulfonyl compound (26) can be prepared according to the methodshown in Scheme XII.

[0265] Further functionalization of 2,3-disubstituted indoles orazaindoles can be readily accomplished by site specific electrophilicsubstitution, and subsequent elaboration at the point of attachment of anewly introduced electrophile. For example, in Scheme XIII,N-bromosuccinimide (NBS) is reacted with compound (17) to introduce abromo radical at the 5-position of (17) affording the bromo derivative(27). The bromo compound (27) can also be used to introduce othersubstituents at the 5-position using methods and reagents well known tothose skilled in the art. Similarly, a fluoro radical can be introducedat the 5-position of (17) through the use of N-fluorobenzenesulfonimideto afford the fluoro derivative (28). Alternatively, a bromo compoundlike (27), or an appropriately 6-amino and indole NH protectedderivative thereof, can be converted into the fluoro derivative bylithium halogen exchange followed by quenching of the lithio anion withN-fluorobenzene sulfonimide (Synlett. 187 (1991) and Tetrahedron Lett.1631 (1992)). These reactions exemplify in a specific fashion thefurther substitution of an azaindole system after the indole has beenformed by electrophilic substitution. In a more general sense, theydemonstrate how other electrophilic agents (for example, iodine,Vilsmeier reagent, nitric acid and the like) can be used to substituteazaindoles and indoles in a specific fashion.

[0266] Further, functionalization of 2,3-disubstituted indoles orazaindoles can be readily accomplished at the indole nitrogen byutilizing the conditions of Mitsunobu wherein an appropriate alcohol isactivated by treatment with triphenylphosphine anddiethylazodicarboxylate (DEAD) and then reacted with the indole orazaindole compound. For example, in Scheme XV, the indole nitrogen of(29) is N-methylated under the Mitsunobu conditions and then reactedwith NBS to afford the 5-bromo-N-1-methylderivative followed bydeprotection affording (32).

[0267] Further, functionalization of 2,3-disubstituted indoles orazaindoles can be readily accomplished by site specific electrophilichalogenation followed by palladium mediated coupling to introduce arylsubstituent. Alternatively, an aryl halide can be converted into an arylstannane by lithium halogen exchange followed by quenching with atrialkylstannyl chloride (for example, tributylstannyl chloride ortrimethylstannyl chloride). The aryl stannane can then be reacted in thepresence of palladium (O) in a coupling process. Those skilled in theart are well versed in the diverse conditions and methods available forpalladium (O) assisted couplings (Palladium Reagents andCatalysts—Innovations in Organic Synthesis by Jiro Tsuji, Wiley (1995);and Palladium Reagents in Organic Syntheses by Heck, Academic Press(1985)).

[0268] Schemes XVI-XXIII illustrate the use of palladium mediatedcouplings to prepare compounds of this invention. For example, bromocompound (31) can be coupled to aniline (other amines work as well, seeBuchwald et al., J. Am. Chem. Soc. 7901 (1994); Buchwald et al., Angew.Chem. Int. Ed. Engl. 1348 (1995); Hartwig et al., J. Am. Chem. Soc. 5969(1994)) in a palladium (0) mediated coupling to afford compound (33) asillustrated in Scheme XVI. Alternatively, compound (31) can be coupledwith an aryl boronic acid to afford a phenyl substituted derivative (43)as illustrated in Scheme XVII

[0269] (see Chem. Lett. 1405 (1989); Bull. Chem. Soc. Jpn 3008 (1988);Synthesis 184 (1989); Tetrahedron Lett 1523 (1990)). Bromo compound (34)can be coupled to a heterocycle like imidazole as exemplified in SchemeXVIII which has been demonstrated in the literature for similar systems((35) plus 2-bromopyridine using tetrakistriphenylphosphine palladium(O), A. S. Bell et al., Tetrahedron Lett. 5013 (1988) and Synthesis 843(1987)). Compound (37) (Scheme IXX) can be prepared from4-amino-2-mercapto-6-methylpyrimidine by conversion to the corresponding2-iodo derivative (iodine and hydrogen iodide in analogy to theconditions of bromine and HBr found in Zh. Org. Khim. (1991) 2235-2236)then converted into (37) in the manner illustrated in Scheme X. TheReformatsky reagent (38) can be coupled to the iodo derivative (37)using tetrakistriphenylphosphine

[0270] palladium (O) as in a similar manner to the previously describedcoupling with 4,6-dimethyl-2-iodopyrimidine (see: Yamanaka et al., Chem.Pharm. Bull. 4309 (1985)). An unnatural amino acid can be prepareddirectly from compound (41) of Scheme XX by reduction (for example,hydrogen gas in the presence of Rh(DIPAMP)). Compound (41) itself can beobtained through a palladium (O) mediated coupling of eneamide (40)directly with bromo derivative (41) utilizing the previously employedconditions for similar transformations (Pd2(dba)3, (o-tol)3P, Et3N,acetonitrile, see J Org. Chem. 2584 (1991); Synthesis 414 (1989); J.Org. Chem. 1289 (1991); Tetrahedron 7151 (1990)). The bromo derivative(31) can be converted to the carboxymethyl derivative (42) asillustrated in Scheme XXI utilizing the previously employed conditionsfor similar transformations (Pd2(dba)3, triphenylphosphine, methanol,carbon monoxide used with 2,6-dichloropyrazine, see Synthesis 923(1990)). An acetylenic group can be directly coupled to the azaindole orindole as illustrated in Scheme XXII utilizing the previously employedconditions for similar transformations (tetrakistriphenylphosphinepalladium (O), CuI, Et3N—see: Synthesis 728 (1984)). Compound (44) canbe obtained utilizing commercially available3-methoxy-4-amino-6-chloro-pyridazine in the manner of Scheme X. Vinylfunctionalization of the appropriate 2,3-disubstituted indoles orazaindoles can be readily

[0271] accomplished as illustrated in Scheme XXIII. Conversion of thebromo derivative (47) of Scheme XXIII to the tributyl stannyl derivativeas described above can be followed by a palladium (O) mediated couplingto a vinyl triflate utilizing the previously employed conditions forsimilar transformations (Pd2(dba)3, Ph3As, NMP, see Tetrahedron Lett.4243 (1991)). Compound (47) can be obtained from 3-amino-2-bromoanilinein a similar manner to Scheme X.

[0272] Further functionalization of the appropriate 2,3-disubstitutedindoles or azaindoles can be readily accomplished by introduction of asulfide group as illustrated in Scheme XXIV or alternatively the thiolcan be introduced prior to indole formation. Examples of thiolintroduction include alkyl thiol (Rumler et al., Pharmazie (1990)657-659) and thiol itself (Pascual et al., Bull. Soc. Chim. Belg.101:297-302 (1992)). For example, the chlorogroup of compound (50) canbe displaced by a thiol reagent. The sulfide (51) can be oxidized to thesulfoxide (52) by treatment with t-butylhydroperoxide in the presence ofthe pyridine (Kagan et al., Tetrahedron asymmetry (1990) 597-610) orfurther oxidized to the sulfone (53) (Trost et al., Tetrahedron Lett(1981) 1287).

[0273] A sulfonamide radical can be introduced prior to the indoleforming process (Schemes I or II) and then further fictionalized asillustrated in Scheme XXV. Reaction of the sulfonamide (56) with excesschloroformates results in formation of compound (57) whereinCR₃=—S(O)₂—NR₂₂—C(O)—OR₂₀ (J. Med. Chem. (1990) 2393-2407). Reaction ofthe sulfonamide (56) with acid chlorides after deprotonation of thesulfonamide with sodium hydride results in formation of compound (58)wherein CR₃=—S(O)₂—NR₂₂—C(O)—R₂₁ (Curran, J. Org. Chem. (1990)4584-4595). Reaction of the sulfonamide (56) with isocyanates results inthe formation of compound (59) wherein CR₃=—S(O)₂—NR₂₂—C(O)—NR₅R₂₁ whereR₅=hydrogen (Howbert et al., J. Med. Chem. (1990) 2393-2407).

[0274] Introduction of the substituent CR₃=—NR₂₂—S(O)₂—NR₅R₂₁ can beaccomplished as illustrated in Scheme XXVI. First, the amino group ofcompound (60) can be alkylated in a reductive amination to affordcompound (61). Then the alkylated amino substituent of compound (61) canbe reacted with o-phenylene sulfate to afford (62) followed by furtherreaction with a second amine as illustrated in Scheme XXVI to affordcompound (63) wherein CR₃=—NR₂₂—S(O)₂—NR₅R₂₁ (Lee et al., Bull. KoreanChem. Soc. (1992), 357).

[0275] Additional methods of indole and azaindole preparation areincluded by reference: G. Gribble Recent Developments in Indole RingSynthesis-Methodology and Applications in Contemporary Organic Synthesisp-145-172; R. Sundberg and P. V. Nguyen Five Membered Ring Systems:Pyrroles and Benzo Derivatives, Chapter 5, Comprehensive HeterocyclicChemistry. It will be understood that these novel compounds are notlimited to the disclosed methods of making them.

[0276] Sulfonyl halides can be prepared by the reaction of a suitablealkyl, aryl, heteroaryl, heterocyclyl and the like Grignard or lithiumreagents with sulfuryl chloride, or sulfur dioxide followed by oxidationwith a halogen, preferably chlorine. Alkyl, aryl, heteroaryl,heterocyclyl and the like Grignard or lithium reagents can be preparedfrom their corresponding halide (such as chloro or bromo) compoundswhich are commercially available or readily prepared from commerciallyavailable starting materials using known methods in the art.Alternatively, mercaptans may be oxidized to sulfonyl chlorides usingchlorine in the presence of water under carefully controlled conditions.Additionally, sulfonic acids may be converted into sulfonyl halidesusing reagents such as PCl₅, SOCl₂, ClC(O)C(O)Cl and the like, and alsoto anhydrides using suitable dehydrating reagents. The sulfonic acidsare either commercially available or may be prepared using procedureswell known in the art from commercially available starting materials. Inplace of the sulfonyl halides, sulfinyl halides or sulfenyl halides canbe utilized to prepare compounds wherein the sulfonyl moiety is replacedby an sulfinyl or thio moiety, respectively. Arylsulfonic acids, benzofused heterocyclyl sulfonic acids or heteroaryl sulfonic acids can beprepared by sulfonation of the aromatic ring by well known methods inthe art, such as by reaction with sulfuric acid, SO₃, SO₃ complexes,such as DMF(SO₃), pyridine(SO₃), N,N-dimethylacetamide(SO₃), and thelike. Preferably, such sulfonyl halides are prepared from such aromaticcompounds by reaction with DMF(SO₃) and SOCl₂ or ClC(O)C(O)Cl. Thereactions may be performed stepwise or in a single pot.

[0277] Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonicacids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans,heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides,heterocyclylhalides, heteroarylhalides, and the like are commerciallyavailable or can be readily prepared from starting materialscommercially available using standard methods well known in the art.

[0278] Thioether derivatives can be converted into the correspondingsulfone or sulfoxide by oxidizing the thioether derivative with asuitable oxidation agent in a suitable solvent. Suitable oxidationagents include, for example, hydrogen peroxide, sodium meta-perborate,oxone (potassium peroxy monosulfate), meta-chloroperoxybenzoic acid,periodic acid and the like, including mixtures thereof Suitable solventsinclude acetic acid (for sodium meta-perborate) and, for other peracids,ethers such as THF and dioxane, and acetonitrile, DMF and the like,including mixtures thereof

[0279] The chemical reactions described above are generally disclosed interms of their broadest application to the preparation of the compoundsof this invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

[0280] Prodrugs of the compounds of this invention are also contemplatedby this invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physicological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers.

[0281] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0282] All reagents were used as received without purification. Allproton and carbon NMR spectra were obtained on either a Varian VXR-300or VXR-400 nuclear magnetic resonance spectrometer.

[0283] The following Examples illustrate the preparation of compounds ofthe present invention and intermediates useful in preparing thecompounds of the present invention.

EXAMPLE 1

[0284]

[0285] Section A

[0286] 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1)

[0287] 4-pyridinecarboxaldehyde (5) (25.0 g, 0.232 mol) was addeddropwise over 1 h to a cooled solution (0° C.) of diphenylphosphite(54.0 g, 0.23 mol) and THF (100 mL). After complete addition, thereaction was allowed to warm to 23° C. After 16 h, the reaction wasconcentrated in vacuo and purified by direct application to flashchromatography (100% ethyl acetate) which afforded4-pyridyl-hydroxymethyldiphenylphosphonate (6): Mass Spectrum (CI) 342(MH+).

[0288] 4-pyridyl-hydroxymethyldiphenylphosphonate (6) (15.3 g, 46 mmol),diethylaniline (4 mL), and phosphorous oxychloride (50 mL) were warmedto 90° C. for 16 h. The reaction was quenched by pouring the reactionmixture over ice (400 g). Potassium carbonate was added until a pH of 8was obtained for the solution followed by extraction with methylenechloride (3×200 mL). After drying ( MgSO4), the reaction wasconcentrated to afford crude 4-pyridyl-chloromethyldiphenylphosphonate(7) as a solid which was used in the next step without furtherpurification: Mass Spectrum (CI) 360 (MH+). Potassium t-butoxide (3.30g, 29.2 mmol) was added as a solid to4-pyridyl-chloromethyldiphenylphosphonate (7) (5.00 g, 13.9 mmol),4-fluorobenzaldehyde (8) (2.00 g, 15.3 mmol), and THF (70 mL) at 23° C.under argon. After 16 h, the reaction was quenched by adding to water(200 mL) over 3 min. After adjusting the pH of the solution to 7 with 1N HCl, the mixture was extracted with ethyl acetate (3×350 mL), anddried (MgSO4). After concentration in vacuo, the residue was purified byflash chromatography (ethyl acetate:methylene chloride 1:1) to afford1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) as a solid: Mass Spectrum(CI) 198 (MH+).

[0289] 3-(4-pyridyl)-2-(4-fluorophenyl)indole (3)

[0290] 2-Iodoaniline (2) (525 mg, 2.40 mmol) was added to palladiumacetate (26.9 mg, 0.120 mmol), triphenyl phosphine (31.5 mg, 0 .120mmol), potassium acetate (1.18 g, 12.0 mmol), tetrabutylammoniumchloride (547 mg, 2.40 mmol), 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1)(1.0 g, 4.8 mmol), and DMF (20 mL). The reaction was warmed to 100° C.for 17 h under argon. After cooling to 23° C., the reaction was pouredinto water (200 mL), extracted with ethyl acetate (3×100 mL), and dried(MgSO4). After concentration in vacuo, the residue was purified by flashchromatography on silica gel (methanol:ethyl acetate 1:19) to affordindoles (3) and (4) as a mixture of regioisomers (4: 1): Mass Spectrum(CI) 289 (MH+).

[0291] Section B

[0292] 4-(2-aminobenzoyl)pyridine (12)

[0293] 4-Bromopyridine (10) (49.38 g, 0.254 mol, free based from thehydrochloride by partitioning between ether and saturated bicarbonate)and diethyl ether (200 mL) was added over 1 h to a cooled solution (−78°C.) of n-butyl lithium (0.381 mol of a 2.5 M solution in hexane) underargon. After 30 min at (−78° C.), magnesium bromide diethyl etherate(98.37 g, 0.381 mol) was added via a dry powder addition funnel. After 1h at −78° C., the reaction mixture was transferred to a jacketedaddition funnel at −50° C., the solution was added to a cooled solution(−50° C.) of anthranilonitrile (15.0 g, 0.127 mol) and benzene (400 mL)over 10 minutes. The reaction was allowed to warm to 23° C. After 16 h,the reaction was poured into 18% sulfuric acid (100 mL), and wasdigested for 1 h. The resultant mixture was extracted with ethyl acetate((400 mL), washed with water (3×400 mL), and dried (MgSO4). Afterconcentration in vacuo, the residue was purified by flash chromatographyin a step gradient fashion (one liter methylene chloride; one literethyl acetate:methylene chloride 1:9; one liter ethyl acetate:methylenechloride 2:8; one liter ethyl acetate:methylene chloride 3:7; one literethyl acetate:methylene chloride 4:6) which afforded4-(2-aminobenzoyl)pyridine (12) as a solid: Mass Spectrum (CI) 199(MH+).

[0294] Alternatively, to a solution of 1-iodo-2-nitrobenzene (3.76 g,15.1 mmol) in dry THF (80 mL) at −78° C. was added n-butyl lithium (7.54mL, 18.9 mmol) over 5 min. After 40 min at −78° C., ethyl isonicotinatewas added in one portion in dry THF (70 mL). After 10 min, the reactionwas allowed to warm to 0° C. for 10 min then quenched with 20 mL ofglacial acetic acid: 30 mL of water. After adjusting the pH to 8 withsaturated bicarbonate solution, the mixture was extracted with ethylacetate (1×500 mL), washed with brine (2×500 mL), dried (Na₂SO₄). Afterconcentration in vacuo, the reaction mixture was treated with 120 mL of5 N NaOH: methanol: water (1:1:1). After removal of methanol in vacuo,the reaction mixture was extracted with ethyl acetate (1×500 mL), thendried (Na₂SO4). After concentration in vacuo, the residue was purifiedby applying flash chromatography (step gradient methylene chloride 100%; the 20% ethyl acetate: methylene chloride: then 40% ethyl acetate:methylene chloride) to afford 4-(2-nitobenzoyl)pyridine.4-(2-Nitrobenzoyl) pyridine (100 mg, 0.44 mmol), stannous chloridedihydrate (297 mg, 1.32 mmol), and 1.1 mL of concentrated hydrochloricacid were warmed to 100° C. for 10 minutes. After cooling to 23° C., thereaction was poured into water (10 mL) and 5 N sodium hydroxide (14 mL)followed by extraction with ethyl acetate (2×50 mL). The ethyl acetatelayer was washed with brine (1×20 mL), dried (Na₂SO₄), and concentratedin vacuo to afford 4-(2-aminobenzoyl)pyridine (12).

[0295] 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14)

[0296] 4-Fluorobenzoyl chloride (78.0 mg, 0.55 mmol) was added to4-(2-aminobenzoyl)pyridine (12) (100 mg, 0.50 mmol), triethylamine (0.35mL, 2.52 mL), and chloroform (5.0 mL) at 23° C. under argon. After 24 hat 23° C., the reaction was poured into water (50 mL), extracted withethyl acetate (3×50 mL), and dried (MgSO4). After concentration invacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14): Mass Spectrum (CI) 321 (MH+).

[0297] 3-(4-pyridyl)-2-(4-fluorophenyl)indole (3)

[0298] Graphite (272 mg, 3.63 mmol) and potassium (100 mg, 0.33 mmol)were warmed to 150° C. under argon in a 250 mL round bottom flask withstirring for 25 min. THF (30 mL) was added via syringe to the hot bronzecolored solid followed by a suspension of titanium (III) chloride (254mg, 1.65 mmol) in THF (20 mL). The resultant black solution was allowedto reflux for 1 h. 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14)(100 mg, 0.33 mmol) and THF (20 mL) were then added to the hot (65° C.)reaction mixture over 5 min. After 1 h at 65° C., the reaction wascooled to 23° C. the filtered through a silica gel pad (20 g). Afterconcentration in vacuo, the residue was purified by flash chromatography(ethyl acetate:methylene chloride 1:1) to afford3-(4-pyridyl)-2-(4-fluorophenyl)indole (3): Mass spectrum (CI) 289(MH+).

[0299] The following compounds were made using the above titanium (0)mediated ring closure with the appropriate acid chlorides to affordamide (X) which was closed to indole XI. It should be noted that in thecase of 2-(3-bromothiophene)carbonyl chloride the amide X contains thebromo atom on the thiophene, but the ring closing (Ti) process removedthe bromo from the thiophene resulting in the hydrido replacement.

R12 MS MS 3-trifluoromethylphenyl 371 (MH+) 339 (MH+) 4-chlorophenyl 335(M − H) 303 (M − H) 3-methylphenyl 315 (M − H) 285 (MH+) 4-pyridyl 304(MH+) 272 (MH+) 1-naphthyl 353 (MH+) 321 (MH+) 2-benzofuranyl 341 (M −H) 311 (MH+) 4-methylsulfinylphenyl 347 (M − H) 2-(3-bromothiophene) 385(M − H) 2-thiophene 275 (M − H)

EXAMPLE 2

[0300]

[0301] 3-(4-fluorophenyl)-2-(4-pyridyl)indole (4)

[0302] A portion of the 4:1 regioisomers from Section A of example 1,compounds (4):(3), was submitted to purification via flashchromatography (100% ethyl acetate) affording (4) in a pure state: MassSpectrum (CI) 289 (MH+).

EXAMPLE 3

[0303]

[0304] 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17)

[0305] 1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone(16) (3.45 g, 10.0 mmol), 2,6-diaminopyridine (1.09 g, 10.0 mmol),p-toluenesulfonic acid monohydrate (13.3 g, 70.0 mmol), and xylene (140mL) were warmed to 60° C. under argon (note: all condensation reactionsof this type were conducted behind an explosion shield). After 1 h at60° C., the reaction was warmed to 135° C. for 3 h. After allowing thereaction to cool to 23° C., the top layer of xylene andp-toluenesulfonic acid was decanted from the bottom layer of gummyproduct residue. The lower product layer was partitioned betweensaturated bicarbonate (100 mL), and ethyl acetate (250 mL). The ethylacetate layer was washed with brine (1×100 mL), and dried (Na2SO4).After concentration in vacuo, the residue was purified by applying flashchromatography (2 liters of ethyl acetate: hexane 7:3 followed by 100%ethyl acetate) to afford the cleanly separated regioisomer (17): MassSpectrum (CI) 305 (MH+).

EXAMPLE 4

[0306]

[0307] 6-Amino-3-(4-fluorophenyl)-2-(4-pyridyl)-7-aza-indole (18)

[0308] A lower RF product from Example 3 was repurified by flashchromatography (100% ethyl acetate) to afford (18) as a solid: MassSpectrum (CI) 305 (MH+).

EXAMPLE 5

[0309]

[0310]6-(4′-t-butoxycarbonylamino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(20)

[0311] General Procedure for mixed anhydride coupling—Isobutylchloroformate (32 ml, 0.24 mmol) was added dropwise to a −20-30° C.solution of 4-t-butoxycarbonyl aminobutyric acid (19) (50.1 mg, 0.247mmol), 4-methylmorpholine (124 ml, 1.23 mmol), and THF (2 mL). After 20min at −20-30° C., 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(17) (75 mg, 0.24 mmol) and THF (3 mL) was added in one portion. Thereaction was allowed to warm to 23° C. After 16 h at 23° C., thereaction was poured into saturated bicarbonate (80 mL), extracted withethyl acetate (2×100 mL), washed with brine (1×100 mL), and dried(Na2SO4). After concentration in vacuo, the residue was purified byapplication to two preparative chromatography plates (silica gel 2 mmthickness, 100% ethyl acetate) to afford6-(4′-t-butoxycarbonylamino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(20) as a solid: Mass Spectrum (CI) 489 (MH+). Ethyl chloroformate canbe used in place of isobutyl chloroformate in this process.

EXAMPLE 6

[0312]

[0313]6-(4′-amino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(21)

[0314] A solution of trifluoroacetic acid:water: anisole (900 ml: 100ml: 39 ml) was added to 6-(4′-t-butoxycarbonylamino-2′-oxo-amino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole(20) (38 mg, 0.078 mmol) at 23° C. After 1 h at 23° C., the reaction wasconcentrated with a stream of nitrogen in a ventilated hood. The residuewas triturated with 2 mL of ether, the resultant solid filtered andwashed with ether (3×2 mL). The TFA salt of (21) was dissolved in 2 mLof water containing 3 equivalents of 1 N HCl and subsequentlyfreeze-dried to afford the HCl salt of6-(4′-amino-2′-oxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(21). The HCl salt was used in biological testing or alternatively thefree base can be used in biological testing which was obtained bypartitioning the hydrochloride salt between ethyl acetate and saturatedbicarbonate. The ethyl acetate layer was dried (Na2SO4), andconcentrated in vacuo to afford6-(4′-amino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(21) as a solid: Mass Spectrum (CI) 389 (MH+).

EXAMPLE 7

[0315]

[0316]6-(5′-ureido-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(26)

[0317] Compound (26) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-citrulline was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(5′-ureido-1′-oxo-2′-t-butoxycarbonylamino-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(26) after preparative plate chromatography: Mass Spectrum (CI) 562(MH+).

EXAMPLE 8

[0318]

[0319]6-(5′-ureido-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(27)

[0320] Compound (27) was prepared from compound (26) in the manner ofexample 6 which afforded6-(5′-ureido-2′-oxo-3′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(27): Mass Spectrum (CI) 462 (MH+).

EXAMPLE 9

[0321]

[0322] 6-(6′-t-Butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28)

[0323] Compound (28) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-e-Boc-lysine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(6′-t-Butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole(28) after preparative plate chromatography: Mass Spectrum (CI) 633(MH+).

EXAMPLE 10

[0324]

[0325]6-(6′-amino-1′-oxo-2′-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(29)

[0326] Compound (29) was prepared from compound (28) in the manner ofexample 6 which afforded6-(6′-amino-1′-oxo-2′-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(29): Mass Spectrum (CI) 433 (MH+).

EXAMPLE 11

[0327]

[0328] 6-(5′-t-Butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)7-aza-indole (30)

[0329] Compound (30) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-d-Boc-ornithine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(5′-t-Butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(30) after preparative plate chromatography: Mass Spectrum (CI) 619(MH+).

EXAMPLE 12

[0330]

[0331]6-(5′-amino-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(31)

[0332] Compound (31) was prepared from compound (30) in the manner ofexample 6 which afforded6-(5′-amino-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(31): Mass Spectrum (CI) 419 (MH+).

EXAMPLE 13

[0333]

[0334] 6-(3′-(4-iodophenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (32)

[0335] Compound (32) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-p-iodo-phenylalanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(3′-(4-iodophenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(32) after preparative plate chromatography: Mass Spectrum (CI) 678(MH+).

EXAMPLE 14

[0336]

[0337]6-(3′-(4-iodophenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(33)

[0338] Compound (33) was prepared from compound (32) in the manner ofexample 6 which afforded6-(3′-(4-iodophenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (33): Mass Spectrum (CI) 578 (MH+).

EXAMPLE 15

[0339]

[0340]6-(3′-Methyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(34)

[0341] Compound (34) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-valine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-Methyl-1′-oxo-2′-t-butoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(34) after preparative plate chromatography: Mass Spectrum (CI) 504(MH+).

EXAMPLE 16

[0342]

[0343]6-(3′-Methyl-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(35)

[0344] Compound (35) was prepared from compound (34) in the manner ofexample 6 which afforded6-(3′-Methyl-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(35): Mass Spectrum (CI) 404 (MH+).

EXAMPLE 17

[0345]

[0346] 6-(4′,4′-Dimethyl-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (36)

[0347] Compound (36) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-b-t-butylalanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(4′,4′-Dimethyl-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(36) after preparative plate chromatography: Mass Spectrum (CI) 532(MH+).

EXAMPLE 18

[0348]

[0349]6-(4′,4′-Dimethyl-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (37)

[0350] Compound (37) was prepared from compound (36) in the manner ofexample 6 which afforded6-(4′,4′-Dimethyl-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (37): Mass Spectrum (CI) 432 (MH+).

EXAMPLE 19

[0351]

[0352]6-(5′-t-butoxycarbonylamino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(38)

[0353] Compound (38) was prepared in the manner of example 5 with thefollowing substitution: N-t-Boc-5-aminovaleric acid was used in place ofN-t-Boc-g-aminobutyric; acid which afforded6-(5′-t-butoxycarbonylamino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole(38) after preparative plate chromatography: Mass Spectrum (CI) 504(MH+).

EXAMPLE 20

[0354]

[0355]6-(5′-amino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(39)

[0356] Compound (39) was prepared from compound (38) in the manner ofexample 6 which afforded6-(5′-amino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(39): Mass Spectrum (CI) 404 (MH+).

EXAMPLE 21

[0357]

[0358]6-(6′-t-butoxycarbonylamino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(40)

[0359] Compound (40) was prepared in the manner of example 5 with thefollowing substitution: N-t-Boc-6-aminocaproic acid was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(6′-t-butoxycarbonylamino-1-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole(40) after preparative plate chromatography: Mass Spectrum (CI) 518(MH+).

EXAMPLE 22

[0360]

[0361]6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(41)

[0362] Compound (41) was prepared from compound (40) in the manner ofexample 6 which afforded6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(41): Mass Spectrum (CI) 418 (MH+).

EXAMPLE 23

[0363]

[0364] 6-(3′-cyclohexyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (42)

[0365] Compound (42) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-b-cyclohexylalanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(3′-cyclohexyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(42) after preparative plate chromatography: Mass Spectrum (CI) 558(MH+).

EXAMPLE 24

[0366]

[0367]6-(3′-cyclohexyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(43)

[0368] Compound (43) was prepared from compound (42) in the manner ofexample 6 which afforded6-(3′-cyclohexyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (43): Mass Spectrum (CI) 458 (MH+).

EXAMPLE 25

[0369]

[0370]6-(4′-t-butoxycarbonyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(44)

[0371] Compound (44) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-b-t-butylglutamic acid was used inplace of N-t-Boc-g-aminobutyric acid which afforded6-(4′-t-butoxycarbonyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(44) after preparative plate chromatography: Mass Spectrum (CI) 590(MH+).

EXAMPLE 26

[0372]

[0373]6-(4′-carboxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(45)

[0374] Compound (45) was prepared from compound (44) in the manner ofexample 6 which afforded6-(4′-carboxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(45): Mass Spectrum (CI) 434 (MH+).

EXAMPLE 27

[0375]

[0376] 6-(3′-O-t-butoxy-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (46)

[0377] Compound (46) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-O-t-butylthreonine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(3′-O-t-butoxy-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(46) after preparative plate chromatography: Mass Spectrum (CI) 562(MH+).

EXAMPLE 28

[0378]

[0379]6-(3′-hydroxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(47)

[0380] Compound (47) was prepared from compound (46) in the manner ofexample 6 which afforded6-(3′-hydroxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(47): Mass Spectrum (CI) 406 (MH+).

EXAMPLE 29

[0381]

[0382] 6-(3′-phenyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (48)

[0383] Compound (48) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-D,L-phenylalanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-O-t-butoxy-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(46) after preparative plate chromatography: Mass Spectrum (CI) 552(MH+).

EXAMPLE 30

[0384]

[0385]6-(3′-phenyl-1′-oxo-2′-D,L-aminoproplamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(49)

[0386] Compound (49) was prepared from compound (48) in the manner ofexample 6 which afforded6-(3′-phenyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(49): Mass Spectrum (CI) 452 (MH+).

EXAMPLE 31

[0387]

[0388] 6-(3′-(4-t-Butoxyphenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (50)

[0389] Compound (50) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-O-t-butyltyrosine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-(4-t-Butoxyphenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (50) afterpreparative plate chromatography: Mass Spectrum (CI) 624 (MH+).

EXAMPLE 32

[0390]

[0391]6-(3′-(4-hydroxyphenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(51)

[0392] Compound (51) was prepared from compound (50) in the manner ofexample 6 which afforded 6-(3′-(4-hydroxyphenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(51): Mass Spectrum (CI) 468 (MH+).

EXAMPLE 33

[0393]

[0394]6-(3′-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(52)

[0395] Compound (52) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-b-alanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(52) after preparative plate chromatography: Mass Spectrum (CI) 476(MH+).

EXAMPLE 34

[0396]

[0397]6-(3′-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(53)

[0398] Compound (53) was prepared from compound (52) in the manner ofexample 6 which afforded6-(3′-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(53): Mass Spectrum (CI) 376 (MH+).

EXAMPLE 35

[0399]

[0400]6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(54)

[0401] Compound (54) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-glycine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(54) after preparative plate chromatography: Mass Spectrum (CI) 461(MH+).

EXAMPLE 36

[0402]

[0403]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(55)

[0404] An HCl dioxane solution (4N, anhydrous, 0.27 mL) was added to6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole(54) (50.0 mg, 0.11 mmol), anisole (59 ml, 0.55 mmol), and dioxane (4mL) in one portion. After 30 min at 23° C., the reaction wasconcentrated with a stream of nitrogen in a hood. The residue wasdiluted with saturated bicarbonate (30 mL), extracted with ethyl acetate(3×50 mL), and dried (Na₂SO₄). After concentration in vacuo, the residuewas purified by application of preparative plate chromatography (two 2mm silica gel plates, ethyl acetate: methanol 19:1) to afford6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (55): Mass Spectrum (CI) 362 (MH+).

EXAMPLE 37

[0405]

[0406]6-(methylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(56)

[0407] Methanesulfonyl chloride (5 ml, 0.07 mmol) was added dropwise to6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (20 mg, 0.066mmol), dimethylamino pyridine (1 mg, 0.007 mmol), and chloroform (3 mL).After 24 h at 23° C., an additional 4 equivalents of methanesulfonylchloride was added. After 4 h at 23° C., NaOH (10N, 3 mL) was added.After 3 h, the mixture was extracted with ethyl acetate (50 mL), washedwith water (3×15 mL), and dried (Na2SO4). After concentration in vacuo,the residue was purified by application of preparative platechromatography (two 2 mm silica gel plates, ethyl acetate) to afford6-(methylsulfonyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(56): Mass Spectrum (CI) 383 (MH+).

EXAMPLE 38

[0408]

[0409]6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (57)

[0410] 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (50mg, 0.164 mmol) and acetic anhydride (0.5 mL) were warmed to 60° C. for1 h. After cooling to 23° C., the reaction was diluted with ethylacetate (50 mL), washed with NaOH (1 N, 50 mL), and dried (Na₂SO₄).Concentration in vacuo afforded6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(57): Mass Spectrum (CI) 347 (MH+).

EXAMPLE 39

[0411]

[0412]6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(58)

[0413] Compound (58) was prepared in the manner of example 37 with thefollowing substitution: 5-chlorothienyl-2-sulfonyl chloride (4equivalents) was used in place of methanesulfonyl chloride whichafforded6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(58) after preparative plate chromatography: Mass Spectrum (CI) 485(MH+).

EXAMPLE 40

[0414]

[0415]6-(Phenylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(59)

[0416] Compound (59) was prepared in the manner of example 37 with thefollowing substitution: phenylsulfonyl chloride (4 equivalents) was usedin place of methanesulfonyl chloride which afforded6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(58) after preparative plate chromatography: Mass Spectrum (CI) 445(MH+).

EXAMPLE 41

[0417]

[0418]6-(2′-N-Phthaloyl-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(60)

[0419] Compound (60) was prepared in the manner of example 5 with thefollowing substitution: N-phthaloylglycine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-N-Phthaloyl-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(60) after preparative plate chromatography: Mass Spectrum (CI) 492(MH+).

EXAMPLE 42

[0420]

[0421]6-(3′-N-Phthaloyl-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(61)

[0422] Compound (60) was prepared in the manner of example 5 with thefollowing substitution: N-phthaloyl-b-alanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-N-Phthaloyl-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(61) after preparative plate chromatography: Mass Spectrum (CI) 506(MH+).

EXAMPLE 43

[0423]

[0424] 3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole (62)

[0425] 1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl) ethanone(16) (5.44 g, 15.77 mmol), 2-aminopyrazine (1.00 g, 1.05 mmol), andconcentrated HCl (30 mL) were heated in a sealed tube to 190° C. behindan explosion shield. After 3 h at 190° C., the reaction was allowed tocool to 23° C. then diluted with water (100 mL). After further dilutionwith concentrated ammonium hydroxide to pH of 12, the reaction wasextracted with methylene chloride (3×200 mL), and dried (MgSO4). Afterconcentration in vacuo, the residue was purified by applying flashchromatography (100% ethyl acetate) to afford3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole (62): Mass Spectrum(CI) 291 (MH+).

EXAMPLE 44

[0426]

[0427]6-(2′-N-t-Butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(63)

[0428] Compound (63) was prepared in the manner of example 5 with thefollowing substitution: N-t-Boc-proline was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-N-t-Butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(63) after preparative plate chromatography: Mass Spectrum (CI) 502(MH+).

EXAMPLE 45

[0429]

[0430]6-(2′-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (64)

[0431] Compound (64) was prepared from compound (63) in the manner ofexample 6 which afforded6-(2′-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (64):Mass Spectrum (CI) 402 (MH+).

EXAMPLE 46

[0432]

[0433]6-(2S′-Dimethylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(65)

[0434] Compound (65) was prepared in the manner of example 5 with thefollowing substitution: N,N-dimethylalanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-Dimethylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(65) after preparative plate chromatography: Mass Spectrum (CI) 404(MH⁺).

EXAMPLE 47

[0435]

[0436]6-(2′-Dimethylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(66)

[0437] Compound (66) was prepared in the manner of example 5 with thefollowing substitution: N,N-dimethylglycine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-Dimethylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(66) after preparative plate chromatography: Mass Spectrum (CI) 389(MH⁺).

EXAMPLE 48

[0438]

[0439]6-(2′-N-Methyl-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(67)

[0440] Compound (67) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-N-methyl-glycine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-N-Methyl-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(67) after preparative plate chromatography: Mass Spectrum (CI) 476(MH+).

EXAMPLE 49

[0441]

[0442]6-(2′-N-Methyl-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(68)

[0443] Compound (68) was prepared from compound (67) in the manner ofexample 6 which afforded6-(2′-N-Methyl-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(68): Mass Spectrum (CI) 376 (MH+).

EXAMPLE 50

[0444]

[0445]6-(4′-N-t-Butoxycarbonylisonipecolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(69)

[0446] Compound (69) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-isonipecotic acid was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(4′-N-t-Butoxycarbonylisonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(69) after preparative plate chromatography: Mass Spectrum (CI) 516(MH+).

EXAMPLE 51

[0447]

[0448]6-(4′-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(70)

[0449] Compound (70) was prepared from compound (69) in the manner ofexample 6 which afforded6-(4′-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(70): Mass Spectrum (CI) 416 (MH+).

EXAMPLE 52

[0450]

[0451]6-(4′-methylsulfoxo-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(71)

[0452] Compound (69) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L-methionine sulfoxide (diasteromericmixture) was used in place of N-t-Boc-g-aminobutyric acid which afforded6-(4′-methylsulfoxo-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (71) afterpreparative plate chromatography: Mass Spectrum (CI) 552 (MH+).

EXAMPLE 53

[0453]

[0454]6-(4′-methylsulfoxo-1′-oxo-2′S-aminobutylamino)-3-(4-pyridyl-2-(4-fluorophenyl)-7-aza-indole(72)

[0455] Compound (72) was prepared from compound (71) in the manner ofexample 6 which afforded6-(4′-methylsulfoxo-1′-oxo-2′S-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (72): Mass Spectrum (CI) 452 (MH+).

EXAMPLE 54

[0456]

[0457] 6-(3′-(3-pyridyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (73)

[0458] Compound (73) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L-b-(3-pyridyl)-alanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(3′-(3-pyridyl)-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(73) after preparative plate chromatography: Mass Spectrum (CI) 553(MH+).

EXAMPLE 55

[0459]

[0460]6-(3′-(3-pyridyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(74)

[0461] Compound (74) was prepared from compound (73) in the manner ofexample 6 which afforded6-(3′-(3-pyridyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (74): Mass Spectrum (CI) 453 (MH+).

EXAMPLE 56

[0462]

[0463]6-(N,N-Di-t-Butoxycarbonyl-L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(75)

[0464] Compound (73) was prepared in the manner of example 5 with thefollowing substitution: 2′-N,N-Di-t-Butoxycarbonyl-L-histidine was usedin place of N-t-Boc-g-aminobutyric acid which afforded6-(2′-N,N-Di-t-Butoxycarbonyl-L-histidinyl)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(75) after preparative plate chromatography: Mass Spectrum (CI) 642(MH+).

EXAMPLE 57

[0465]

[0466]6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (76)

[0467] Compound (76) was prepared from compound (75) in the manner ofexample 6 which afforded6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(76): Mass Spectrum (CI) 542 (MH+).

EXAMPLE 58

[0468]

[0469]6-(N-t-Butoxycarbonyl-3(S)1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(114)

[0470] Compound (114) was prepared in the manner of example 5 with thefollowing substitution: N-t-Butoxycarbonyl-3(S)1′,2′,3′,4′-tetrahydro-3-isoquinolinylcarboxylic acid was used in placeof N-t-Boc-g-aminobutyric acid which afforded 6-(N-t-Butoxycarbonyl-3(S)1′,2′3′,4′-tetrahydro-3′-isoquinolinyloxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(114) after preparative plate chromatography: Mass Spectrum (CI) 564(MH+).

EXAMPLE 59

[0471]

[0472] 6-(3(S)1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxoamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (115)

[0473] Compound (115) was prepared from compound (114) in the manner ofexample 6 which afforded 6-(3(S)1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxoamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(115): Mass Spectrum (CI) 464 (MH+).

EXAMPLE 60

[0474]

[0475] 6-(2′-phenyl-1′-oxo-2′R—N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (116)

[0476] Compound (116) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-R-phenylglycine was used in place ofN—t-Boc-g-aminobutyric acid which afforded6-(2′-phenyl-1′-oxo-2′R-N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (116) afterpreparative plate chromatography: Mass Spectrum (CI) 538 (MH⁺).

EXAMPLE 61

[0477]

[0478]6-(2′-phenyl-1′-oxo-2′R-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(117)

[0479] Compound (117) was prepared from compound (116) in the manner ofexample 6 which afforded6-(2′-phenyl-1′-oxo-2′R-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(117): Mass Spectrum (CI) 438 (MH⁺).

EXAMPLE 62

[0480]

[0481] 6-(2′-phenyl-1′-oxo-2′S—N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (118)

[0482] Compound (118) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-S-phenylglycine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(2′-phenyl-1′-oxo-2′S—N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (118) afterpreparative plate chromatography: Mass Spectrum (CI) 538 (MH⁺).

EXAMPLE 63

[0483]

[0484]6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(119)

[0485] Compound (119) was prepared from compound (118) in the manner ofexample 6 which afforded6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(119): Mass Spectrum (CI) 438 (MH⁺).

EXAMPLE 64

[0486]

[0487]6-(2′-phenyl-1′-oxo-2′R—N-t-butoxycarbonyl-N-methylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(120)

[0488] Compound (120) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-R—N-methylphenyl glycine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(2′-phenyl-1′-oxo-2′R—N-t-butoxycarbonyl-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(120) after preparative plate chromatography: Mass Spectrum (CI) 552(MH⁺).

EXAMPLE 65

[0489]

[0490]6-(2′-phenyl-1′-oxo-2′R—N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(121)

[0491] Compound (121) was prepared from compound (120) in the manner ofexample 6 which afforded6-(2′-phenyl-1′-oxo-2′R—N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (121): Mass Spectrum (CI) 452 (MH⁺).

EXAMPLE 66

[0492]

[0493]6-(1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(122)

[0494] Compound (122) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L-alanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (122) afterpreparative plate chromatography: Mass Spectrum (CI) 476 (MH⁺).

EXAMPLE 67

[0495]

[0496]6-(1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl-7-aza-indole(123)

[0497] Compound (123) was prepared from compound (122) in the manner ofexample 6 which afforded6-(1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(123): Mass Spectrum (CI) 376 (MH⁺).

EXAMPLE 68

[0498]

[0499] 6-(3′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (124)

[0500] Compound (124) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L-phenylalanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (124)after preparative plate chromatography: Mass Spectrum (CI) 552 (MH⁺).

EXAMPLE 69

[0501]

[0502]6-(3′-phenyl-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(125)

[0503] Compound (125) was prepared from compound (124) in the manner ofexample 6 which afforded6-(3′-phenyl-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (125):Mass Spectrum (CI) 452 (MH⁺).

EXAMPLE 70

[0504]

[0505] 6-(1′-oxo-2′S-t-butoxycarbonyl-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (126)

[0506] Compound (126) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L—N-methylalanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (126)after preparative plate chromatography: Mass Spectrum (CI) 489 (MH+).

EXAMPLE 71

[0507]

[0508]6-(1′-oxo-2′S—N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(127)

[0509] Compound (127) was prepared from compound (126) in the manner ofexample 6 which afforded6-(1′-oxo-2′S—N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(127): Mass Spectrum (CI) 389 (MH⁺).

EXAMPLE 72

[0510]

[0511]6-(1′-oxo-2′S-t-butoxycarbonyl-N-methyl-4-methyl-2-aminopentyl-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(128)

[0512] Compound (128) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L—N-methylleucine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(1′-oxo-2′S-t-butoxycarbonyl-N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(128) after preparative plate chromatography: Mass Spectrum (CI) 532(MH⁺).

EXAMPLE 73

[0513]

[0514]6-(1′-oxo-2′S—N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(129)

[0515] Compound (129) was prepared from compound (128) in the manner ofexample 6 which afforded6-(1′-oxo-2′S—N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(129): Mass Spectrum (CI) 432 (MH⁺).

EXAMPLE 74

[0516]

[0517]6-(1′-oxo-2′R-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(130)

[0518] Compound (130) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-D-alanine was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(1′-oxo-2′R-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (130) afterpreparative plate chromatography: Mass Spectrum (CI) 476 (MH⁺).

EXAMPLE 75

[0519]

[0520]6-(1′-oxo-2′R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(131)

[0521] Compound (131) was prepared from compound (130) in the manner ofexample 6 which afforded6-(1′-oxo-2′R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(131): Mass Spectrum (CI) 376 (MH⁺).

EXAMPLE 76

[0522]

[0523] 6-(3′-(2-thienyl)-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (132)

[0524] Compound (132) was prepared in the manner of example 5 with thefollowing substitution: N-Boc-L-b-(2-thienyl) alanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(3′-(2-thienyl)-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(132) after preparative plate chromatography: Mass Spectrum (CI) 558(MH⁺).

EXAMPLE 77

[0525]

[0526]6-(3′-(2-thienyl)-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(133)

[0527] Compound (133) was prepared from compound (132) in the manner ofexample 6 which afforded6-(3′-(2-thienyl)-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(133): Mass Spectrum (CI) 458 (MH⁺).

EXAMPLE 78

[0528]

[0529] 6-(3′-(4-azidophenyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (134)

[0530] Compound (134) was prepared in the manner of example 5 with thefollowing substitution:(3′-(4-azidophenyl)-1′-oxo-2′S-t-butoxycarbonylaminopropionic acid wasused in place of N-t-Boc-g-aminobutyric acid which afforded6-(3′-(4-azidophenyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (134) afterpreparative plate chromatography: Mass Spectrum (CI) 609 (MH⁺).

EXAMPLE 79

[0531]

[0532]6-(3′-(4-azidophenyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(135)

[0533] Compound (135) was prepared from compound (134) in the manner ofexample 6 which afforded6-(3′-(4-azidophenyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (135): Mass Spectrum (CI) 509 (MH⁺).

EXAMPLE 80

[0534]

[0535] 6-(3′-(3-benzothienyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (136)

[0536] Compound (136) was prepared in the manner of example 5 with thefollowing substitution:3-(3′-benzothienyl)-1-oxo-2S-t-butoxycarbonylaminopropionic acid wasused in place of N-t-Boc-g-aminobutyric acid which afforded6-(3′-(3-benzothienyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (136) afterpreparative plate chromatography: Mass Spectrum (CI) 608 (MH⁺).

EXAMPLE 81

[0537]

[0538]6-(3′-(3-benzothienyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(137)

[0539] Compound (137) was prepared from compound (136) in the manner ofexample 6 which afforded6-(3′-(3-benzothienyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(137):Mass Spectrum (CI) 508 (MH⁺).

EXAMPLE 82

[0540]

[0541]6-(4′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(138)

[0542] Compound (138) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-L-homophenylalanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(4′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(138) after preparative plate chromatography: Mass Spectrum (CI) 566(MH⁺).

EXAMPLE 83

[0543]

[0544]6-(4′-phenyl-1′-oxo-2′-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(139)

[0545] Compound (139) was prepared from compound (138) in the manner ofexample 6 which afforded6-(4′-phenyl-1′-oxo-2′-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(139): Mass Spectrum (CI) 466 (MH⁺).

EXAMPLE 83B

[0546]

[0547] 5-bromo-3-(4-pyridyl)-2-(3-trifluoromethylphenyl)indole

[0548] 3-(4-pyridyl)-2-(3-trifluoromethylphenyl)indole was treated withNBS in the same manner as6-amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole to affordthe title compound: Mass Spectrum (CI) 417 (MBr⁸¹—H).

EXAMPLE 84

[0549]

[0550]6-(4′-phenyl-1′-oxo-2′-(D)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(140)

[0551] Compound (140) was prepared in the manner of example 5 with thefollowing substitution: N-a-t-Boc-D-homophenylalanine was used in placeof N-t-Boc-g-aminobutyric acid which afforded6-(4′-phenyl-1′-oxo-2′-(D)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(140) after preparative plate chromatography: Mass Spectrum (CI) 566(MH⁺).

EXAMPLE 85

[0552]

[0553]6-(4′-phenyl-1′-oxo-2′-(D)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(141)

[0554] Compound (141) was prepared from compound (140) in the manner ofexample 6 which afforded6-(4′-phenyl-1′-oxo-2′-(D)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(141): Mass Spectrum (CI) 466 (MH⁺).

EXAMPLE 86

[0555]

[0556]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole(143)

[0557]6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(29) (50 mg, 0.108 mmol), isobutyl chloroformate (42 ml, 0.325 mmol),N-methylmorpholine (119 ml, 1.08 mmol), potassium carbonate (74.9 mg,0.542 mmol), and DMF (4 mL) were warmed at 80° C. for 16 h. Aftercooling to 23 C., the reaction was diluted with water (20 mL), extractedwith ethyl acetate (2×20 mL), and dried (Na2SO4). After concentration invacuo, the residue was purified by preparative plate chromatography toafford6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole(142). Compound (104) was converted to6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole(143) in the manner of example 6: Mass Spectrum (CI) 462 (MH⁺).

EXAMPLE 87

[0558]

[0559]6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(144)

[0560] 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (100mg, 0.329 mmol), benzaldehyde (100 ml, 0.987 mmol), and1,2-dichloroethane (20 mL) were allowed to stir for 15 min followed bythe addition of sodium triacetoxyborohydride (139 mg, 0.658 mmol) as asolid. After 16 h at 23° C., the reaction was partitioned between ethylacetate (200 mL) and satd bicarbonate (80 mL). The organic layer waswashed with brine (80 mL), and dried (Na2SO4). After concentration invacuo, a portion of the residue was purified by preparativechromatography to afford 6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (144):Mass Spectrum (CI) 395 (MH⁺).

EXAMPLE 88

[0561]

[0562]6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(145)

[0563] Compound (145) was prepared in the manner of example 87 with thefollowing substitution: acetaldehyde was used in place of benzaldehydewhich afforded6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (145)after preparative plate chromatography: Mass Spectrum (CI) 361 (MH⁺).

EXAMPLE 89

[0564]

[0565]6-(3′-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(146)

[0566] Compound (146) was prepared in the manner of example 87 with thefollowing substitution: phenylhydrocinnam-aldehyde was used in place ofbenzaldehyde which afforded6-(3′-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(146) after preparative plate chromatography: Mass Spectrum (CI) 423(MH⁺).

EXAMPLE 90

[0567]

[0568]6-(2′(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(147)

[0569] Compound (147) was prepared in the manner of example 87 with thefollowing substitution: 2′-phenylpropionaldehyde was used in place ofbenzaldehyde which afforded6-(2′(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(147) after preparative plate chromatography: Mass Spectrum (CI) 423(MH⁺).

EXAMPLE 91

[0570]

[0571]6-(2′(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(148)

[0572] Compound (148) was prepared in the manner of example 87 with thefollowing substitution: 2′-ethylhexanaldehyde was used in place ofbenzaldehyde which afforded6-(2′(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(148) after preparative plate chromatography: Mass Spectrum (CI) 417(MH⁺).

EXAMPLE 92

[0573]

[0574] 6-Amino-5-chloro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(149)

[0575] Compound (149) was prepared in the manner of example 3 with thefollowing substitution: 3-chloro-2,6-diaminopyridine was used in placeof 2,6-diaminopyridine which afforded after6-Amino-5-chloro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (149)after flash chromatography: Mass Spectrum (CI) 439 (MH⁺).

EXAMPLE 93

[0576]

[0577] 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(28)

[0578] 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250mg, 0.822 mmol), N-fluorobenzenesulphonamide (259 mg, 0.822 mmol), andDMF (4 mL) were warmed to 90° C. behind an explosion shield. After 48 h,the reaction was concentrated in vacuo and the residue was purified byflash chromatography (ethyl acetate: hexane 1:1) to afford6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28):Mass Spectrum (CI) 323 (MH⁺).

EXAMPLE 94

[0579]

[0580] 6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(27)

[0581] 6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250mg, 0.822 mmol), N-bromosuccinamide (146 mg, 0.822 mmol), and DMF (4 mL)were allowed to stir at 23° C. After 24 h, the reaction was concentratedin vacuo and the residue was purified by flash chromatography (ethylacetate:hexane 1:1) to afford6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (27): MassSpectrum (CI) 385 (MH⁺Br⁸¹).

EXAMPLE 95

[0582]

[0583] 6-(di-isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(150)

[0584] Compound (150) was prepared in the manner of example 87 with thefollowing substitution: 3-methylbutyraldehyde was used in place ofbenzaldehyde which afforded6-(di-isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (150)after preparative plate chromatography: Mass Spectrum (CI) 445 (MH⁺).

EXAMPLE 96

[0585]

[0586]6-(2′,2′-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(151)

[0587] Compound (151) was prepared in the manner of example 87 with thefollowing substitution: pivaldehyde was used in place of benzaldehydewhich afforded6-(2′,2′-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(151) after preparative plate chromatography: Mass Spectrum (CI) 375(MH⁺).

EXAMPLE 97

[0588]

[0589] 6-(isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (152)

[0590] Compound (152) was prepared in the manner of example 87 with thefollowing substitution: 3-methylbutyraldehyde was used in place ofbenzaldehyde which afforded6-(isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (152)after preparative plate chromatography: Mass Spectrum (CI) 375 (MH⁺).

EXAMPLE 98

[0591]

[0592]6-(2′-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(153)

[0593] Compound (153) was prepared in the manner of example 87 with thefollowing substitution: 2-ethylbutyraldehyde was used in place ofbenzaldehyde which afforded6-(2′-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(153) after preparative plate chromatography: Mass Spectrum (CI) 389(MH⁺).

EXAMPLE 99

[0594]

[0595]6-(2′-thienylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(154)

[0596] Compound (154) was prepared in the manner of example 87 with thefollowing substitution: 2-thiophene carboxaldehyde was used in place ofbenzaldehyde which afforded6-(2′-thienylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(154) after preparative plate chromatography: Mass Spectrum (CI) 401(MH⁺).

EXAMPLE 100

[0597]

[0598]6-(3′,3′di-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(155)

[0599] Compound (155) was prepared in the manner of example 87 with thefollowing substitution: phenylhydrocinnam-aldehyde was used in place ofbenzaldehyde which afforded6-(3′,3′di-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(155) after preparative plate chromatography: Mass Spectrum (CI) 541(MH⁺).

EXAMPLE 101

[0600]

[0601] 6-(ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(156)

[0602] Compound (156) was prepared in the manner of example 87 with thefollowing substitution: acetaldehyde was used in place of benzaldehydewhich afforded6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (156)after preparative plate chromatography: Mass Spectrum (CI) 361 (MH⁺).

EXAMPLE 102

[0603]

[0604]6-(3′-phenyl-1′-oxo-2′-(R,S)-methylpropylamino)-3-(4-pyridyl-2-(4-fluorophenyl)-7-aza-indole(157)

[0605] Compound (157) was prepared in the manner of example 5 with thefollowing substitution: 3-phenyl-2-methylpropionic acid was used inplace of N-t-Boc-g-aminobutyric acid which afforded6-(3′-phenyl-1′-oxo-2′-(R,S)-methylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(157) after preparative plate chromatography: Mass Spectrum (CI) 451(MH⁺).

EXAMPLE 103

[0606]

[0607]6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole(158)

[0608] To a solution of6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(29) (50.0 mg, 0.108 mmol), triphenylphosphine (85 mg, 0.325 mmol),methanol (13 ml, 0.791 mmol) and methylene chloride (5 mL) was addeddiethyl azodicarboxylate (51 ml, 0.325 mmol) at 0° C. The reaction wasallowed to warm to 23° C. After 2.5 h, an additional 2 equivalents ofmethanol, triphenylphosphine, and diethyl azodicarboxylate were added.After 16 h, the reaction was concentrated in vacuo and the residue waspurified by preparative plate chromatography to afford6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole(30) which was converted to6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole(158) as described in example 6: Mass Spectrum (CI) 376 (MH⁺).

EXAMPLE 104

[0609]

[0610]6-(3′,3′-dimethyl-1-oxo-butylamino)-3-(4pyridyl-2-(4-fluorophenyl)-7-aza-indole(159)

[0611] Compound (159) was prepared in the manner of example 5 with thefollowing substitution: 3,3-dimethylbutyric acid was used in place ofN-t-Boc-g-aminobutyric acid which afforded6-(3′,3′-dimethyl-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(159) after preparative plate chromatography: Mass Spectrum (CI) 403(MH⁺).

EXAMPLE 105

[0612]

[0613]6-(ethoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(160)

[0614] Compound (160) was obtained as a side product from example 104wherein a small amount of unreacted ethyl chloroformate resulted inacylation of the 6-amino function to afford6-(ethoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(160) after preparative plate chromatography: Mass Spectrum (CI) 377(MH⁺).

EXAMPLE 106

[0615]

[0616]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole(161)

[0617] Compound (161) was prepared in the manner of example 87 with thefollowing substitution: 6-(2′S-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indolewas used in place of6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indolewhich afforded6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole (161) after preparative platechromatography: Mass Spectrum (CI) 390 (MH+).

EXAMPLE 107

[0618]

[0619]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole(162) Compound (162) was prepared in the manner of example 87 with thefollowing substitutions: 6-(2′S-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indolewas used in place of6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indoleand isobutanol was used in place of methanol which afforded6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole(162) after preparative plate chromatography: Mass Spectrum (CI) 432(MH⁺).

EXAMPLE 108

[0620]

[0621]6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-cyclohexylmethyl-7-aza-indole(163)

[0622] Compound (163) was prepared in the manner of example 87 with thefollowing substitutions:6-(2′S-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indolewas used in place of6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indoleand cyclohexymethanol was used in place of methanol which afforded6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole(163) after preparative plate chromatography: Mass Spectrum god 472(MH⁺).

EXAMPLE 109

[0623] Using the procedures of the above general description and theabove examples, the compounds of Tables 1-7 can be prepared. TABLE 1

R X₄ R X₄ butyl CH methyl C—CH3 ethyl N ethyl C—CH(OH)CH3 propyl CHpropyl C—CH2OH isopropyl N isopropyl C—N(CH3)2 hydroxymethyl Nhydroxymethyl C—OCH3 hydroxyethyl CH hydroxyethyl C—CH3 benzyl N benzylC—OCF3 4-methoxybenzyl N 4-methoxybenzyl C—OH 4-iodobenzyl CH4-iodobenzyl C—CH3 4-pyridylmethyl N 4-pyridylmethyl C—CH33-pyridylmethyl CH 3-pyridylmethyl C—OH 2-pyridyhnethyl N2-pyridylmethyl C—OCH3 methylthioethyl N methylthioethyl C—CF3methylsulfonylethyl CH methylsulfonylethyl C—F methylsulfinylethyl Nmethylsulfinylethyl C—CH(OH)CH3 imidazolylmethyl C—CH3 imidazolylmethylC—OCH3

[0624] TABLE 2

R₁₁ X₃ R₁₁ X₃ 4-pyridyl C—F 4-(2-amino- C—CH3 imidazoyl) 4-pyridyl N4-(2-amino- C—CH(OH)CH3 imidazoyl) 4-pyridyl C—Br 4-quinolinyl C—CH2OH4-quinolinyl N 4-pyridyl C—N(CH3)2 4-(2-aminopyridyl) C—F 4-pyridylC—OCH3 4-(2-aminopyridyl) C—CF3 4-quinolinyl C—CH3 4-(2-aminopyridyl) N4-pyridyl C—OCF3 4-quinolinyl C—F 4-pyridyl C—OH 4-quinolinyl C—CF34-(2-aminopyridyl) C—CH3 4-pyridyl C—Ph 4-pyridyl C—CH3 4-quinolinylC—Ph 4-quinolinyl C—OH 4-(2-aminopyridyl) C—Ph 4-quinolinyl C—OCH34-quinolinyl C—Cl 4-pyridyl C—CF3 4-(2-aminopyridyl) C—Cl 4-(2-acetami-C—F dopyridyl) 4-(2-aminoimidazoyl) C—F 4-pyridyl C—CH(OH)CH34-(2-aminoimidazoyl) C—Br 4-(2-aminopyridyl) C—OCH3 4-pyrimidinyl C—CF34-pyrimidinyl C—CH3 4-pyrimidinyl N 4-pyrimidinyl C—OH 4-pyrimidinyl C—F4-pyrimidinyl C—OCH3 4-pyrimidinyl C—Cl 4-pyrimidinyl C—CH(OH)CH34-pyrimidinyl C—Ph 4-pyrimidinyl C—Br

[0625] TABLE 3

R₁₁ R₄₀ 4-pyridyl —NH2 4-pyridyl —NHPh 4-pyridyl —NHCH3 4-quinolinyl—NH(4-MeOPh) 4-(2-aminopyridyl) —NH2 4-(2-aminopyridyl) —NHPh4-(2-aminopyridyl) —NHCH3 4-quinolinyl —NH2 4-quinolinyl —NHPh 4-pyridyl—NH(4-MeOPh) 4-quinolinyl —CH2N(CH3)2 4-(2-aminopyridyl) —CH2N(CH3)24-quinolinyl —CH2CH2N(CH3)2 4-(2-aminopyridyl) —CH2NH24-(2-aminoimidazoyl) —CH2CH2N(CH3)2 4-(2-aminoimidazoyl) —CH2N(CH3)24-pyrimidinyl —NH2 4-pyrimidinyl —NHPh 4-pyrimidinyl —NHCH34-pyrimidinyl —NH(4-MeOPh) 4-pyrimidinyl —Ph 4-(2-aminoimidazoyl) —CH34-(2-aminoimidazoyl) —Ph 4-quinolinyl —Ph 4-pyridyl —Ph 4-pyridyl2-thienyl 4-quinolinyl —CH2NH2 4-pyridyl n-Bu 4-pyridyl —CH2N(CH3)24-(2-aminopyridyl) —CH3 4-pyridyl —CH3 4-quinolinyl —CH3 4-quinolinyln-propyl 4-pyridyl —CH2CH2N(CH3) 4-(2-acetamidopyridyl) —CH2CH2N(CH3)24-pyridyl —CH2NH2 4-(2-aminopyridyl) —CH2NH2 4-pyrimidinyl 2-thienyl4-pyrimidinyl —CH2NH2 4-pyrimidinyl n-Bu 4-pyrimidinyl —CH2N(CH3)24-pyrimidinyl —CH3

[0626] TABLE 4

R₁₀ X₃ R₁₀ X₃ methyl CH methyl C—CH3 ethyl N ethyl C—CH(OH)CH3 propyl CHpropyl C—CH2OH isopropyl N isopropyl C—N(CH3)2 —C(O)Ph N benzyl C—OCH3—C(O)NH2 CH —C(O)NH2 C—CH3 benzyl N 4-methoxybenzyl C—OCF34-methoxybenzyl N 4-iodobenzyl C—OH —C(O)NHPh CH 4-pyridylmethyl C—CH3—C(O)NHEt N 3-pyridylmethyl C—CH3 —C(O)Ph CH —C(O)Ph C—OH —C(O)NH2 N—C(O)NHEt C—OCH3 methyl N ethyl C—CF3 ethyl CH methyl C—F isobutyl N—C(O)NH2 C—CH(OH)CH3 methyl C—CH3 methyl C—OCH3

[0627] TABLE 5

R₁₂ X₃ R₁₂ X₃ phenyl CH 3-chlorophenyl C—CH3 phenyl N 3-chlorophenylC—CH(OH)CH3 3-chlorophenyl CH 4-fluorophenyl C—CH2OH 3-chlorophenyl N4-fluorophenyl C—N(CH3)2 4-fluorophenyl N 3-methylthiophenyl C—OCH34-fluorophenyl CH 3-methylthiophenyl C—CH3 1-naphthyl N3-methylsulfinyl- C—OCF3 phenyl 2-naphthyl N 4-cyanophenyl C—OH3-methylthiophenyl CH 4-carboxami- C—CH3 dophenyl 3-methylthiophenyl N4-fluorophenyl C—CH3 1-naphthyl CH 3,4-dichlorophenyl C—OH3,4-dichlorophenyl N 3-methylthiophenyl C—OCH3 3-trifluoro- N3,4-dichlorophenyl C—CF3 methylphenyl 3,4-dichlorophenyl CH4-fluorophenyl C—F 4-methoxyphenyl N 4-methoxyphenyl C—CH(OH)CH34-methoxyphenyl C-CH3 4-methoxyphenyl C—OCH3

[0628] TABLE 6

R₄₁ X₃ R₄₁ X₃ methyl CF methyl C—CH3 —CH2NH2 N —CH2NH2 C—CH(OH)CH32-(5-chlorothienyl) C—Br 2-(5-chlorothienyl) C—CH2OH —CH2NMe2 N —CH2NMe2C—N(CH3)2 phenyl C—F phenyl C—OCH3 methyl C—CF3 methyl C—CH3 l-naphthylN 1-naphthyl C—OCF3 2-(5-chlorothienyl) C—F 2-(5-chlorothienyl) C—OH—CH2CH2NH2 C—CF3 —CH2CH2NH2 C—CH3 phenyl C—Ph 4-carboxymethyl- C—CH3phenyl methyl C—Ph 4-n-butoxyphenyl C—OH —CH2NH2 C—Ph 1-naphthyl C—OCH3phenyl C—Cl methyl C—CF3 methyl C—Cl —CH2NH2 C—F methyl C—F methylC—CH(OH)CH3 —CH2NH2 C—Br —CH2CH2NH2 C—OCH3 n-butyl C—CF3(1-piperidinyl)- C—CH3 propyl 4-methoxyphenyl N (1-piperizinyl)- C—OHphenyl 4-cyanophenyl C—F 2-(5-chlorothienyl) C—OCH3 4-n-butoxyphenylC—Cl —CH2NH2 C—CH(OH)CH3 methyl C—Ph n-butyl C—Br

[0629] TABLE 7

X₂ X₃ —C—C(O)Ph C—F —C—C(O)NHMe N —C—C(O)NHMe C—Br —C—S(O2)—Et N—C—C(O)—Bu C—F —CH C—CF3 —C—S(O2)—NHEt N —C—NH—S(O2)—NHCH3 C—F—C—C(O2)Me C—CF3 —CH C—Ph —C—S(O2)—Et C—Ph —C—C(O)Ph C—Ph —CH C—Cl—C—NHEt C—Cl —C—NHPr C—F —CH C—Br —C—NHMe C—CF3 —C—C(O)NHPh N—C—N(Me)—C(O)—Me C—F —C—N—S(O2)Me C—Cl —C—NHEt C—Ph N C—CH3 C—FC—CH(OH)CH3 C—CF3 C—CH2OH N C—N(CH3)2 C—Br C—OCH3 N C—CH3 —CH C—OCF3 —CHC—OH C—C(O2)Me C—CH3 —CH C—CH3 —CH C—OH C—NHEt C—OCH3 —CH C—CF3 —CH C—F—CH C—CH(OH)CH3 —CH C—OCH3 —CH C—CH3 C—C(O2)Me C—OH C—F C—OCH3 C—CF3C—CH(OH)CH3 C—S(O2)—Et C—Br

[0630] TABLE 8

X₂ X₃ —C—NH—C(O)Me C—F —C—C(O)NHMe N —C—C(O)NHMe C—Br —C—NH—S(O2)Me N—C—C(O)—Bu C—F —CH C—CF3 —C—NH(CO)CH2NH2 N —C—NH—S(O2)—NHCH3 C—F—C—C(O2)Me C—CF3 —CH C—Ph —C—S(O2)—Et C—Ph —C—C(O)Ph C—Ph —CH C—Cl—C—NHEt C—Cl —C—NHPr C—F —CH C—Br —C—NHMe C—CF3 —C—C(O)NHPh N—C—NH—S(O2)Me C—F —C—N—S(O2)Me C—Cl —C—NHEt C—Ph N C—CH3 C—F C—CH(OH)CH3C—CF3 C—CH2OH N C—N(CH3)2 C—Br C—OCH3 N C—CH3 —CH C—OCF3 —CH C—OHC—C(O2)Me C—CH3 —CH C—CH3 —CH C—OH C—NHEt C—OCH3 —CH C—CF3 —CH C—F —CHC—CH(OH)CH3 —CH C—OCH3 —CH C—CH3 C—C(O2)Me C—OH C—F C—OCH3 C—CF3C—CH(OH)CH3 C—S(O2)—Et C—Br

[0631] TABLE 9

X₂ X₃ —C—NH—C(O)Me C—F —C—C(O)NHMe N —C—C(O)NHMe C—Br —C—NH—S(O2)Me N—C—C(O)—Bu C—F —CH C—CF3 —C—NH(CO)CH2NH2 N —C—NH—C(O)CH(Me)NH2 C—F—C—C(O2)Me C—CF3 —CH C—Ph —C—S(O2)—Et C—Ph —C—C(O)Ph C—Ph —CH C—Cl—C—NHEt C—Cl —C—NHPr C—F —CH C—Br —C—NHMe C—CF3 —C—C(O)NHPh N—C—NH—S(O2)Me C—F —C—N—S(O2)MeC —Cl —C—NHEt C—Ph C—F C—CH(OH)CH3 C—CF3C—CH2OH N C—N(CH3)2 C—Br C—OCH3 N C—CH3 —CH C—OCF3 —CH C—OH C—C(O2)MeC—CH3 —CH C—C(O)H —CH C—OH C—NHEt C—OCH3 —CH C—CF3 —CH C—F —CHC—CH(OH)CH3 —CH C—OCH3 —CH C—CH3 C—C(O2)Me C—OH C—F C—OCH3 C—CF3C—CH(OH)CH3 C—S(O2)—Et C—Br

[0632] TABLE 10

X₂ X₃ —C—NH—C(O)Me C—F —C—C(O)NHMe N —C—C(O)NHMe C—Br —C—NH—S(O2)Me N—C—C(O)—Bu C—F —CH C—CF3 —C—NH(CO)CH2NH2 N —C—NH—C(O)CH(Me)NH2 C—F—C—C(O2)Me C—CF3 —CH C—Ph —C—S(O2)—Et C—Ph —C—C(O)Ph C—Ph —CH C—Cl—C—NHEt C—Cl —C—NHPr C—F —CH C—Br —C—NHMe C—CF3 —C—C(O)NHPh N—C—NH—S(O2)Me C—F —C—N—S(O2)Me C—Cl —C—NHEt C—Ph N C—CH3 C—F C—CH(OH)CH3C—CF3 C—CH2OH N C—N(CH3)2 C—Br C—OCH3 N C—CH3 —CH C—OCF3 —CH C—OHC—C(O2)Me C—CH3 —CH C—C(O)H —CH C—OH C—NHEt C—OCH3 —CH C—CF3 —CH C—F —CHC—CH(OH)CH3 —CH C—OCH3 —CH C—CH3 C—C(O2)Me C—OH C—F C—OCH3 C—CF3C—CH(OH)CH3 C—S(O2)—Et C—Br

EXAMPLE 110

[0633] The following assays were used to characterize the ability ofcompounds of the invention to inhibit the production of TNF-α andIL-1-β. The second assay measured the inhibition of TNF-α and/or IL-1-βin mice after oral administration of the test compounds. The thirdassay, a glucagon binding inhibition in vitro assay, can be used tocharacterize the ability of compounds of the invention to inhibitglucagon binding. The fourth assay, a Cyclooxygenase enzyme (COX-1 andCOX-2) inhibition activity in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit COX-1 and/or COX-2.

Lipopolysaccharide-activated Monocyte TNF Production Assay

[0634] Isolation of Monocytes

[0635] Test compounds were evaluated in vitro for the ability to inhibitthe production of tumor necrosis factor (TNF) by monocytes activatedwith bacterial lipopolysaccharide (LPS). Fresh residual sourceleukocytes (a byproduct of plateletpheresis) were obtained from thelocal blood bank and peripheral blood mononuclear cells (PBMCs) wereisolated by density gradient centrifugation on Ficol-Paque Plus(Pharmacia). PBMCs were suspended at 2×10⁶/ml in DMEM supplemented tocontain 2% FCS (10 mM), 0.3 mg/ml glutamate, 100 U/ml penicillin G and100 mg/ml streptomycin sulfate (complete media). Cells were plated intoFalcon flatbottom 96 well culture plates (200 μl/well) and culturedovernight at 37° C. and 6% CO₂. Nonadherent cells were removed bywashing with 200 μl/well of fresh medium. Wells containing adherentcells (˜70% monocytes) were replenished with 100 μl of fresh medium.

[0636] Preparation of Test Compound Stock Solutions

[0637] Test compounds were dissolved in DMZ. Compound stock solutionswere 2 5 prepared to an initial concentration of 10-50 μM. Stocks werediluted initially to 20-200 μM in complete media. Nine two-fold serialdilutions of each compound were then prepared in complete medium.

[0638] Treatment of Cells with Test Compounds and Activation of TNFProduction with Lipopolysaccharide

[0639] One hundred microliters of each test compound dilution were addedto microtiter wells containing adherent monocytes and 100 μl completemedium. Monocytes were cultured with test compounds for 60 min at whichtime 25 μl of complete medium containing 30 ng/ml lipopolysaccharidefrom E. coli K532 were added to each well. Cells were cultured anadditional 4 hrs. Culture supernatants were then removed and TNF presentin the supernatants was quantified using an ELISA.

[0640] TNF ELISA

[0641] Flat bottom 96 well Corning High Binding ELISA plates were coatedovernight (4° C.) with 150 μL/well of 3 μg/ml murine anti-human TNFa MAb(R&D Systems #MAB210). Wells were then blocked 1 h at room temperaturewith 200 μL/well of CaCl₂-free ELISA buffer supplemented to contain 20mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl2, 0.15mM thimerosal, pH 7.4). Plates were washed and replenished with 100 μlof test supernatants (diluted 1:3) or standards. Standards consisted ofeleven 1.5-fold serial dilutions from a stock of 1 ng/ml recombinanthuman TNF (R&D Systems). Plates were incubated at room temperature for 1h on orbital shaker (300 rpm), washed and replenished with 100 μl/wellof 0.5 μg/ml goat anti-human TNFa (R&D systems #AB-210-NA) biotinylatedat a 4:1 ratio. Plates were incubate for 40 min, washed and replenishedwith 100 μl/well of alkaline phosphatase-conjugated streptavidin(Jackson ImmunoResearch #016-050-084) at 0.02 μg/ml. Plates wereincubated 30 min, washed and replenished with 200 μl/well of 1 mg/ml ofp-nitrophenyl phosphate. After 30 min, plates were read at 405 nm on aVmax plate reader.

[0642] Data Analysis

[0643] Standard curve data were fit to a second order polynomial andunknown TNF-a concentrations determined from their OD by solving thisequation for concentration. TNF concentrations were then plotted Vs testcompound concentration using a second order polynomial. This equationwas then used to calculate the concentration of test compounds causing a50% reduction in TNF production.

[0644] The following compounds had an IC₅₀ of less than 20 μM:3-(4-pyridyl)-2-(4-fluorophenyl)indole (3);6-amino-3-(4-fluorophenyl)-2-(4-pyridyl)-7-aza-indole (18);6-(4′-t-butoxycarbonylamino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(21); 6-(4′-amino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (22);6-(5′-ureido-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(64);6-(5′-ureido-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(65);6-(6′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(66);6-(6′-amino-1′-oxo-2′-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(67);6-(4′-amino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(22); 6-(5′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (68);6-(5′-amino-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(69);6-(3′-Methyl-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(73);6-(4′,4′-Dimethyl-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (75);6-(5′-amino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(77);6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(79);6-(3′-cyclohexyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(81);6-(4-carboxy-1′-oxo-2-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(83); 6-(3′-hydroxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (85);6-(3′-phenyl-1′-oxo-2′-D,L-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(87); 6-(3′-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (91);6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(29);6-(methylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(93);6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(94);6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(95);6-(3′-N-phthaloyl-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(98); 3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole (99);6-(2′-N-t-Butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(100);6-(2′-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(101);6-(2′-Dimethylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(103);6-(4′-methylsulfoxo-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(108);6-(4′-methylsulfoxo-1′-oxo-2′S-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(109);6-(3′-(3-pyridyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(110);6-(3′-(3-pyridyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(111);6-(N,N-Di-t-butoxycarbonyl-L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(112);6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(113);6-(3(S)1′,2′,3′,4′-tetrahydro-3-isoquinolinyloxoamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(115);6-(3′-phenyl-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(125);6-(1′-oxo-2′S-N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(129);6-(3′-(2-thienyl)-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(133);6-(3′-(4-azidophenyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(135);6-(3′-(3-benzothienyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(137);6-(4′-phenyl-1′-oxo-2′-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(139); 6-(4′-indole (141);6-(2-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)1-isobutoxycarbonyl-7-aza-indole (143);6-(2′(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (147);6-(2′(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(148); 6-amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(28); 6-amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(27); 6-(2′,2′-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (151);6-(isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (152);6-(2′-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(153);6-(2′-thienylmethylamino)-3-(4-pyridyl)-²-(4-fluorophenyl)-7-aza-indole(154); 6-(ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(156); and6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole(158).

[0645] The following compounds had an IC₅₀ of less than 1 μM:6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17);6-(3′-(4-iodophenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(71);6-(3′-(4-hydroxyphenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(89);6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(92);6-(2S′-dimethylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(102);6-(2′-N-methyl-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(104);6-(2′-N-methyl-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(105);6-(4′-N-t-butoxycarbonylisonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(106); 6-(4-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (107);6-(2′-phenyl-1′-oxo-2′R-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(117);6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(119);6-(2′-phenyl-1′-oxo-2′R-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (121); 6-(1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (123);6-(1′-oxo-2′S-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(127); and6-(1′-oxo-2′R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole(131).

[0646] In a similar manner to the above described assay involving theLPS induced release of TNF-a from monocytes, compounds of this inventioncan also be shown to inhibit LPS induced release of IL-1beta, IL-6and/or IL-8 from monocytes by measuring concentrations of IL-1beta, IL-6and/or IL-8 by methods well known to those skilled in the art.

[0647] Selected compounds from this invention have demonstratedantiinflammatory properties in models of inflammation including thecarageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol.Med. (1962) vol 111, p 544; K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Antiinflammatory Agents, Chemistry and Pharmacology,Vol. 13-II, Academic, New York, 1974, p. 33) and collagen inducedarthritis (D. E. Trentham et al J. Exp. Med. (1977) vol. 146, p 857; J.S. Courtenay, Nature (New Biol.) (1980), Vol 283, p 666). Also, selectedcompounds from the class have shown in vivo activity in a LPS mousemodel in which serum levels of TNF-a were reduced in the presence ofcompounds of this invention.

Inhibition of LPS-Induced TNF-α Production in Mice

[0648] Male DBA/1LACJ mice were dosed with vehicle or test compounds ina vehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30minutes prior to lipopolysaccharide (2 mg/kg, I.V.) injection. Ninetyminutes after LPS injection, blood was collected and the serum wasanalyzed by ELISA for TNF levels.

¹²⁵I-Glucagon Binding Screen with CHO/hGLUR Cells

[0649] The assay is described in WO 97/16442, which is incorporatedherein by reference in its entirety.

[0650] Reagents

[0651] The reagents can be prepared as follows: (a) prepare fresh 1Mo-Phenanthroline (Aldrich) (198.2 mg/ml ethanol); (b) prepare fresh 0.5MDTT (Sigma); (c) Protease Inhibitor Mix (1000×): 5 mg leupeptin, 10 mgbenzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per mlDMSO and store aliquots at −20° C.; (d) 250 μM human glucagon(Peninsula): solubilize 0.5 mg vial in 575 μl 0.1N acetic acid (1 μlyields 1 μM final concentration in assay for non-specific binding) andstore in aliquots at −20° C.; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1mM DTT and 3 mM o-phenanthroline; (f) Assay Buffer with 0.1% BSA (fordilution of label only; 0.01% final in assay): 10 μl 10% BSA(heat-inactivated) and 990 μl Assay Buffer; (g) ¹²⁵I-Glucagon (NEN,receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 μl in assaybuffer with BSA (about 50 pM final concentration in assay).

[0652] Harvesting of CHO/hGLUR Cells for Assay

[0653] 1. Remove media from confluent flask then rinse once each withPBS (Ca, Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media,Inc.).

[0654] 2. Add 10 ml Enzyme-free Dissoc. Fluid and hold for about 4 min.at 37° C.

[0655] 3. Gently tap cells free, triturate, take aliquot for countingand centrifuge remainder for 5 min. at 1000 rpm.

[0656] 4. Resuspend pellet in Assay Buffer at 75000 cells per 100 μl.

[0657] Membrane preparations of CHO/hGLUR cells can be used in place ofwhole cells at the same assay volume. Final protein concentration of amembrane preparation is determined on a per batch basis.

[0658] Assay

[0659] The determination of inhibition of glucagon binding can becarried out by measuring the reduction of I¹²⁵-glucagon binding in thepresence of compounds of Formula I. The reagents are combined in 120 μLof assay buffer as follows: CHO/ Compound/ 250 μM hGLUR Vehicle Glucagon¹²⁵I-Glucagon Cells Total Binding + —/5 μl — 25 μl 100 μl Compound 5μl/— — 25 μl 100 μl Nonspecific —/5 μl 1 μl 25 μl 100 μl Binding

[0660] The mixture is incubated for 60 min. at 22° C. on a shaker at 275rpm. The mixture is filtered over pre-soaked (0.5% polyethylimine (PEI))GF/C filtermat using an Innotech Harvester or Tomtec Harvester with fourwashes of ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity in thefilters is determined by a gamma-scintillation counter.

[0661] In a similar manner to the above described assay involving theLPS induced release of TNF-a from monocytes, compounds of this inventioncan also be shown to inhibit LPS induced release of IL-1beta, IL-6and/or IL-8 from monocytes by measuring concentrations of IL-1beta, IL-6and/or IL-8 by methods well known to those skilled in the art.

Cyclooxygenase Enzyme Activity Assay

[0662] The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10%FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

[0663] COX-1 Assay

[0664] In preparation for the COX-1 assay, THP-1 cells are grown toconfluency, split 1:3 into RPMI containing 2% FBS and 10 mM phorbol12-myristate 13-acetate (TPA), and incubated for 48 hours on a shaker toprevent attachment. Cells are pelleted and resuspended in Hank'sBuffered Saline (HBS) at a concentration of 2.5×10⁶ cells/mL and platedin 96-well culture plates at a density of 5×10⁵ cells/mL. Test compoundsare diluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours.

[0665] Arachidonic acid is added to a final concentration of 30 mM, thecells incubated for 20 minutes at 37° C., and enzyme activity determinedas described below.

[0666] COX-2 Assay

[0667] For the COX-2 assay, subconfluent HOSC are trypsinized andresuspended at 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL,plated in 96-well tissue culture plates at a density of 3×10⁴ cells perwell, incubated on a shaker for 1 hour to evenly distribute cells,followed by an additional 2 hour static incubation to allow attachment.The media is then replaced with MEM containing 2% FBS (MEM-2% FBS) and 1ng human IL-1b/mL, and the cells incubated for 18-22 hours. Followingreplacement of media with 190 mL MEM, 10 mL of test compound diluted inHBS is added to achieve the desired concentration and the cellsincubated for 4 hours. The supernatants are removed and replaced withMEM containing 30 mM arachidonic acid, the cells incubated for 20minutes at 37° C., and enzyme activity determined as described below.

[0668] COX Activity Determined

[0669] After incubation with arachidonic acid, the reactions are stoppedby the addition of 1 N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls.

[0670] The following compounds exhibit activities in the Cyclooxygenaseassay with IC₅₀ values of 20 μM or less:6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole; and 6-(1′-oxo-2′S-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole.

[0671] The following compounds exhibit activities in the Cyclooxygenaseassay with IC₅₀ values of 5 μM or less:6-(3′-phenyl-1′-oxo-2′-D,L-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(methyl sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;and 3-(4-pyridyl)-2-(4-fluorophenyl)indole.

[0672] This invention further relates to the use of a compound of thisinvention in the manufacture of a medicament for the prophylaxis andtreatment, either acutely or chronically, of TNF-a mediated diseasestates. In addition, the compounds of this invention are useful in themanufacture of a medicament for treating disease states in which IL-1,IL-6 and/or IL-8 play a role. Also, the compounds of this invention areuseful in the manufacture of a analgesic medicament and a medicament fortreating pain disorders, such as hyperalgesia. The compounds of thepresent invention also are useful in the manufacture of a medicament toprevent the production of prostaglandins by inhibition of enzymes in thehuman arachidonic acid/prostaglandin pathway.

[0673] This invention also relates to a pharmaceutical compositioncomprising a compound of this invention and a pharmaceuticallyacceptable carrier, and if desired other active ingredients. Thecompounds of this invention are administered by any suitable route,preferably in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds of the presentinvention required to arrest the progress or prevent tissue damageassociated with the disease are readily ascertained by one of ordinaryskill in the art.

[0674] All of the compounds of this invention are useful in theprophylaxis and treatment of TNF-a mediated disease states. Thecompounds are also useful in the prophylaxis and treatment of diseasestates in which IL-1, IL-6, and IL-8 play a role. Preferably, thecompounds of this invention are useful in the prophylaxis and treatmentof rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; antiviraltherapy including those viruses sensitive to TNF-a inhibition—HIV-1,HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and theherpes viruses including HSV-1, HSV-2, and herpes zoster; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; braintrauma; atherosclerosis; Alzheimer's discease; multiple sclerosis;cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever andmylagias due to infection.

[0675] In addition to inhibiting the production of TNF-a, compounds ofthis invention can also reduce levels of other cytokines including butnot limited to IL-1, IL-6 or IL-8. Reducing elevated levels of theseinflammatory cytokines to basal levels or below is favorable incontrolling, slowing progression, or possibly alleviating many diseasestates.

[0676] The present invention provides a method of treating a diseasestate in which cytokine levels are elevated which comprisesadministering an effective amount of a compound of this invention.Compounds of this invention are of use in the prophylaxis and acute orchronic therapy of any disease state in a human, or other mammal, whichis exacerbated by or mediated by elevated or unregulated IL-1, IL-6,IL-8 and/or TNF-a production by such mammal's cells, such as, but notlimited to monocytes, macrophages, and glial cells. More preferably,this invention relates to a method of lowering the levels of TNF-aand/or IL-1 in a mammal in need thereof which comprises administering aneffective dose of a compound of this invention or a pharmaceuticalcomposition thereof. In addition, this invention relates to a method oflowering the levels of IL-6 and/or IL-8 in a mammal in need thereofwhich comprises administering an effective dose of a compound of thisinvention or a pharmaceutical composition thereof.

[0677] Accordingly, the compounds of this invention or a pharmaceuticalcomposition thereof are useful in the treatment or prophylaxis of anumber of disease states including rheumatoid arthritis; Pagets disease;osteophorosis; multiple myeloma; uveititis; acute and chronicmyelogenous leukemia; pancreatic β cell destruction; osteoarthritis;rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease;adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease;allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis;asthma; muscle degeneration; cachexia; Reiter's syndrome; type I andtype II diabetes; bone resorption diseases; graft vs. host reaction;ischemia reperfusion injury; atherosclerosis; brain trauma; Alzheimer'sdisease; stroke; toxic shock syndrome; fever, and myalgias due toinfection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster, all of which are sensitive to TNF-α and/or IL-1 inhibition orglucagon antagonism, will also be positively effected by the compoundsand methods of the invention.

[0678] The compounds of the present invention also may possess analgesicproperties and may be useful for the treatment of pain disorders, suchas hyperalgesia due to excessive IL-1. The compounds of the presentinvention may also prevent the production of prostaglandins byinhibition of enzymes in the human arachidonic acid/prostaglandinpathway, including cyclooxygenase (WO 96/03387, incorporated herein byreference in its entirety).

[0679] Because of their ability to lower TNF-α and IL-1 concentrationsor inhibit glucagon binding to its receptor, the compounds of theinvention are also useful research tools for studying the physiologyassociated with blocking these effects.

[0680] In another aspect, this invention comprises the use of a compoundof the invention, or pharmaceutically acceptable salts thereof, in themanufacture of a medicament for the treatment either acutely orchronically of a TNF-α, IL-1β, IL-6, and/or IL-8 mediated disease state,including those described previously.

[0681] In still another aspect, this invention provides a pharmaceuticalcomposition comprising an effective TNF-α, IL-1β, IL-6, and/or IL-8lowering amount and/or effective plasma glucose level lowering amount ofa compound of the invention and a pharmaceutically acceptable carrier ordiluent, and if desired other active ingredients. The compounds of theinvention are administered by any suitable route, preferably in the formof a pharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds of the present invention required to arrest the progressor prevent tissue damage associated with the disease are readilyascertained by one of ordinary skill in the art using standard methods.

[0682] For the treatment of TNF-α, IL-1β, IL-6, and IL-8 mediateddiseases and/or hyperglycemia, the compounds of the present inventionmay be administered orally, parentally, by inhalation spray, rectally,or topically in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles. The termparenteral as used herein includes, subcutaneous, intravenous,intramuscular, intrasternal, infusion techniques or intraperitoneally.

[0683] For the prophylaxis and treatment of disease states, thecompounds of the present invention may be administered orally,parentally, or by inhalation spray, rectally, or topically in dosageunit formulations containing conventional pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereinincludes, subcutaneous, intravenous, intramuscular, intrasternal,infusion techniques or intraperitoneally.

[0684] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.

[0685] The dosage regimen for treating a disease state with thecompounds of this invention and/or compositions of this invention isbased on a variety of factors, including the type of disease, the age,weight, sex and medical condition of the patient, the severity of thecondition, the route of administration, pharmacological considerationssuch as the activity, efficacy, pharmacokinetic and toxicology profilesof the particular compound employed, whether a drug delivery system isutilized and whether the compound is administered as part of a drugcombination. Thus the dosage regimen may vary widely. Dosage levels ofthe order from about 0.01 mg to 80 mg per kilogram of body weight perday, preferably from about 0.5 mg to 30 mg/kg, more preferably fromabout 1 mg to 15 mg/kg are useful for all methods of use disclosedherein. The pharmaceutically active compounds of this invention can beprocessed in accordance with convential methods of pharmacy to producemedicinal agents for administration to patients, mammals includinghumans.

[0686] For oral administration, the pharmaceutical composition may be inthe form of, for example, a capsule, a tablet, a suspension, or liquid.The pharmaceutical composition is preferably made in the form of adosage unit containing a given amount of the active ingredient. Forexample, these may about 25 to 150 mg. A suitable daily dose for a humanor other mammal may vary widely depending on the condition of thepatient and other factors.

[0687] The compounds of this invention may also be administered byinjection as a composition with suitable carriers including saline,dextrose, or water. The daily parenteral dosage regimen wll be fromabout 0.1 to about 80 mg/kg of total body weight, preferably from about0.5 to about 30 mg/kg, and more preferably from about 1 mg to 15 mg/kg.

[0688] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0689] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0690] A suitable topical dose of compounds of this invention is 0.1 mgto 150 mg administered one to four, preferably two or three times daily.For topical administration, the active ingredient may comprise from0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation,although it may comprise as much as 10% w/w, but preferably not morethan 5% w/w, and more preferably from 0.1% to 1% of the formulation.Formulations suitable for topical administration include liquid orsemi-liquid peparations suitable for penetration through the skin suchas liniments, lotions, ointments, creams, or pastes and drops suitablefor administration to the eye, ear, or nose.

[0691] For administration, the compounds of this invention areordinarily combined with one or more adjuvants appropriate for theindicated route of administration. The compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,stearic acid, talc, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodiumalginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tabletedor encapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, benzyl alcohol, and/orvarious buffers. Other adjuvants and modes of administration are wellknown in the pharmaceutical art. The carrier or diluent may include timedelay material, such as glyceryl monostearate or glyceryl distearatealone or with a wax, or other materials well known in the art.

[0692] The pharmaceutical compositions may be made up in a solid formincluding granules, powders or suppositories or in a liquid form such assolutions, suspensions, or emulsions. The pharmaceutical compositionsmay be subjected to conventional pharmaceutical operations such assterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

[0693] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0694] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents,

[0695] Compounds of the present invention can possess one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of thisinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of thisinvention can likewise be obtained by utilizing optically activestarting materials. These isomers may be in the form of a free acid, afree base, an ester or a salt.

[0696] The compounds of the present invention can be used in the form ofsalts derived from inorganic or organic acids. These salts include butare not limited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0697] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

[0698] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more other agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

[0699] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[0700] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein X₁ is N, CH orCR₁; X₂ is N, CH or CR₂; X₃ is N, CH or CR₃; and X₄ is N, CH or CR₄;provided that at least one of X₁, X2, X₃ and X₄ is N or CH, and that notmore than two of X₁, X2, X₃ and X₄ are N; wherein R₁, R₂, R₃ and R₄ areeach independently —Z—Y, provided that (1) R₂ and R₄ are not bothsubstituted or unsubstituted amino radicals; (2) the total number ofaryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is0-3; and (3) the combined total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R₁, R₂, R₃ and R4 is 0-4; wherein each Z isindependently a (1) bond; (2) alkyl, alkenyl or alkynyl radicaloptionally substituted by (a) 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano or halo, and (b) 1-2 radicals ofheterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicalsof amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl orhaloalkyl; (3) heterocyclyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; or (4) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, halo, alkyl or haloalkyl; each Y is independently a(1) hydrogen radical, provided Z is other than a bond; (2) halo, cyanoor nitro radical; (3) —C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁ or—C(NR₅)—NR₅R₂₁ radical; (4) —OR₂₁, —O—C(O)—R₂₁, —O—C(O)—NR₅R₂₁ or—O—C(O)—NR₂₂—S(O)₂—R₂₀ radical; (5) —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀,—S(O)₂—NR₅R₂₁, —S(O)₂—NR₂₂—C(O)—R₂₁, S(O)₂—NR₂₂—C(O)—OR₂₀ or—S(O)₂—NR₂₂—C(O)—NR₅R₂₁ radical; or (6) —NR₅R₂₁, —NR₂₂—C(O)—R₂₁,—NR₂₂—C(O)—OR₂₀, —NR₂₂—C(O)—NR₅R₂₁, —NR₂₂—C(NR₅)—NR₅R₂₁, —NR₂₂—S(O)₂—R₂₀or —NR₂₂—S(O)₂—NR₅R₂₁ radical; wherein each R₅ is independently (1)hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy,alkoxy, alkylthio, cyano or halo; or (3) aryl, heteroaryl, aralkyl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl orcycloalkylalkyl radicals optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano,alkyl or haloalkyl; and wherein each R₂₀ is independently (1) alkyl,alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of—CO₂R₂₃, amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio,aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl or haloalkyl; (2) heterocyclyl radicaloptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;or (3) aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy,alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₂ is independently (1)hydrogen radical; (2) alkyl radical optionally substituted by a radicalof heterocyclyl, aryl or heteroaryl optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or (3)heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and eachR₂₃ is independently hydrogen or alkyl, or aryl, heteroaryl, aralkyl orheteroaralkyl optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and R₁₀ is a hydrogen,R₃₀, —C(O)—R₂₉, —C(O)—OR₃₀, —C(O)—NR₃₁R₃₂, —S(O)₂—R₃₀ or —S(O)₂—NR₃₁R₃₂radical, R₁₁ and R₁₂ are each independently an aryl or heteroarylradical optionally substituted by 1-3 radicals of (1) R₃₀; (2) halo orcyano radicals; (3) —C(O)—R₃₀, —C(O)—OR₂₉, —C(O)—NR₃₁R₃₂ or—C(NR₃₁)—NR₃₁R₃₂ radicals; (4) —OR₂₉, —O—C(O)—R₂₉, —O—C(O)—NR₃₁R₃₂ or—O—C(O)—NR₃₃—S(O)₂—R₃₀ radicals; (5) —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀,—S(O)₂—NR₃₁R₃₂, —S(O)₂—NR₃₃—C(O)—R₃₀, —S(O)₂—NR₃₃—C(O)—OR₃₀ or—S(O)₂—NR₃₃—C(O)—NR₃₁R₃₂ radicals; or (6) —NR₃₁R₃₂, —NR₃₃—C(O)—R₂₉,—NR₃₃—C(O)—OR₃₀, —NR₃₃—C(O)—NR₃₁R₃₂, —NR₃₃—C(NR₃₁)—NR₃₁R₃₂,—NR₃₃—S(O)₂—R₃₀ or —NR₃₃—S(O)₂—NR₃₁R₃₂ radicals; provided that the totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicalssubstituted on each of R₁₁ and R₁₂ is 0-1; wherein each R₃₀ isindependently (1) alkyl, alkenyl or alkynyl radicals optionallysubstituted by 1-3 radicals of —NR₃₁R₃₁, —CO₂R₂₃, hydroxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy,aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo,alkyl or haloalkyl; (2) heterocyclyl radical optionally substituted by1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, halo, alkyl or haloalkyl; each R₂₉ is independentlyhydrogen radical or R₃₀; each R₃₁ and R₃₂ are each independently (1)hydrogen radicals; (2) alkyl radical optionally substituted by ancycloalkyl, aryl, heterocyclyl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, alkyl or haloalkyl; or (3) aryl, heteroaryl,heterocyclyl or cycloalkyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; and wherein each R₃₃ is independently (1)hydrogen radical; or (2) alkyl radical optionally substituted by aradical of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,cyano, alkyl or haloalkyl; and provided that when each of X₁, X₂, X₃ andX₄ represent carbon atoms, then R₁₁ is a substituted aryl radical andR₁₂ is heteroaryl radical, or R₁₁ is a heteroaryl radical and R₁₂ is asubstituted aryl radical.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein X₁ is N, CH or CR₁; X₂is N, CH or CR₂; X₃ is N, CH or CR₃; and X₄ is N, CH or CR₄; providedthat at least one of X₁, X₂, X₃ and X₄ is N or CH, and that not morethan two of X₁, X₂, X₃ and X₄ are N; wherein R₁, R₂, R₃ and R₄ are eachindependently —Z—Y, provided that (1) R₂ and R₄ are not both substitutedor unsubstituted amino radicals; (2) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (3) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₁, R₂, R₃ and R₄ is 0-4; each Z isindependently a (1) bond; (2) C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈alkynyl radical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, or heterocyclyl, aryl or heteroaryloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (3)heterocyclyl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (4) aryl or heteroaryl radical optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₄ haloalkyl of 1-3 halo radicals; each Y is independently a (1)hydrogen radical, provided Z is other than a bond; (2) halo, cyano ornitro radical; (3) —C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁ or —C(NR₅)—NR₅R₂₁radical; (4)—OR₂₁, —O—C(O)—R₂₁, —O—C(O)—NR₅R₂₁ or —O—C(O)—NR₂₂—S(O)₂—R₂₀radical; (5) —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀, —S(O)₂—NR₅R₂₁,—S(O)₂—NR₂₂—C(O)—R₂₁, —S(O)₂—NR₂₂—C(O)—OR₂₀ or —S(O)₂—NR₂₂—C(O)—NR₅R₂₁radical; or (6) —NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—C(O)—OR₂₀,—NR₂₂—C(O)—NR₅R₂₁, —NR₂₂—C(NR₅)—NR₅R₂₁, —NR₂₂—S(O)₂—R₂₀ or—NR₂₂—S(O)₂—NR₅R₂₁ radical; each R₅ is independently (1) hydrogenradicals; (2) C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano orhalo; or (3) aryl, heteroaryl, aryl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl,heterocyclyl, heterocyclyl-C₁-C₄-alkyl, C₃-C₈ cycloalkyl orC₃-C₈-cycloalkyl-C₁-C₄-alkyl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of1-3 halo radicals; each R₂₀ is independently (1) C₁-C₈ alkyl, C₂-C₈alkenyl or C₂-C₈ alkynyl radicals optionally substituted by 1-3 radicalsof —CO₂R₂₃, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-(C₁-C₄alkoxy)carbonyl)—N-C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (2) heterocyclyl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, azido, C₁—C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; eachR₂₁ is independently hydrogen radical or R₂₀; each R₂₂ is independently(1) hydrogen radical; (2) C₁-C₄ alkyl radical optionally substituted bya radical of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; each R₂₃ is independently hydrogen orC₁-C₄ alkyl, or aryl, heteroaryl, aryl-C₁-C₄-alkyl orheteroaryl-C₁-C₄-alkyl optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; R₁₀ is a hydrogen,R₃₀, —C(O)—R₂₉, —C(O)—OR₃₀, —C(O)—NR₃₁R₃₂, —S(O)₂—R₃₀ or —S(O)₂—NR₃₁R₃₂radical; R₁₁ and R₁₂ are each independently an aryl or heteroarylradical optionally substituted by 1-3 radicals of (1) R₃₀; (2) halo orcyano radicals; (3) —C(O)—R₃₀, —C(O)—OR₂₉, —C(O)—NR₃₁R₃₂ or—C(NR₃₁)—NR₃₁R₃₂ radicals; (4) —OR29, —O—C(O)—R₂₉, —O—C(O)—NR₃₁ R₃₂ or—O—C(O)—NR₃₃—S(O)₂—R₃₀ radicals; (5) —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀,—S(O)₂—NR₃₁R₃₂, —S(O)₂—NR₃₃—C(O)—R_(S(O)) ₂—NR₃₃—C(O)—OR₃₀ or—S(O)₂—NR₃₃—C(O)—NR₃₁R₃₂ radicals; or (6) —NR₃₁R₃₂, —NR₃₃—C(O)—R₂₉,—NR₃₃—C(O)—OR₃₀, —NR₃₃—C(O)—NR₃₁R₃₂, —NR₃₃—C(NR₃₁)—NR₃₁R₃₂,—NR₃₃—S(O)₂—R₃₀ or —NR₃₃—S(O)₂—NR₃₁R₃₂ radicals; provided that the totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicalssubstituted on each of R₁₁ and R₁₂ is 0-1; each R₃₀ is independently (1)C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl radicals optionallysubstituted by 1-3 radicals of —NR₃₁R₃₁, —CO₂R₂₃, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, haloor aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; each R₂₉ isindependently hydrogen radical or R₃₀; each R₃₁ and R₃₂ are eachindependently (1) hydrogen radicals; (2) C₁-C₄ alkyl radical optionallysubstituted by an C₃-C₈ cycloalkyl, aryl, heterocyclyl or heteroarylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) aryl, heteroaryl, heterocyclyl or C₃-C₈ cycloalkylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; and each R₃₃ is independently (1) hydrogen radical; or (2)C₁-C₄ alkyl radical optionally substituted by a radical of heterocyclyl,aryl or heteroaryl optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; and wherein heterocyclyl is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals; aryl is aphenyl or naphthyl radical; and heteroaryl is radical of a monocyclic orbicyclic aromatic heterocyclic ring system having 5-6 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 3. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein each Z isindependently a (1) bond; (2) C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈alkynyl radical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (3) heterocyclylradical optionally substituted by 1-2 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; or(4) aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₄ haloalkyl of1-3 halo radicals; each R₅ is independently (1) hydrogen radicals; (2)C₁-C₄ alkyl, C₂-C₅ alkenyl or C₂-C₅ alkynyl radicals optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or halo;or (3) aryl, heteroaryl, aryl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl,heterocyclyl, heterocyclyl-C₁-C₄-alkyl, C₃-C₈ cycloalkyl orC₃-C₈-cycloalkyl-C₁-C₄-alkyl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of1-3 halo radicals; each R₂₀ is independently (1) C₁-C₈ alkyl, C₂-C₅alkenyl or C₂-C₅ alkynyl radicals optionally substituted by 1-3 radicalsof —CO₂R₂₃, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-(C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; (2) heterocyclyl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; or(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicalsof amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₃₀ is independently (1)C₁-C₄ alkyl radical optionally substituted by 1-3 radicals of (a)—NR₃₁R₃₁; (b) C₁-C₄ alkoxy-carbonyl or phenoxycarbonyl orphenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino,alkylamino, di-(C₁-C₄-alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl; or (c)hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or phenyl-C₁-C₄-alkoxy,phenyl-C₁-C₄-alkylthio, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₄ haloalkyl of 1-3 halo radicals; (2) C₁-C₄ haloalkyl of 1-3 haloradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; eachR₂₉ is independently hydrogen radical or R₃₀; each R₃₁ is independently(1) hydrogen radicals; or (2) C₁-C₄ alkyl radical optionally substitutedby an phenyl or heteroaryl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl or trifluoromethyl radicals; and each R₃₂is independently (1) hydrogen radicals; (2) C₁-C₄ alkyl radicaloptionally substituted by an C₃-C₆ cycloalkyl, aryl, heterocyclyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; or (3) aryl, heteroaryl, heterocyclyl or C₃-C₆ cycloalkylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl or C₁-C₄ haloalkyl of 1-3 haloradicals; and each R₃₃ is independently hydrogen or C₁-C₄ alkyl radical.4. The compound of claim 3 or a pharmaceutically acceptable saltthereof, wherein R₁, R₂, R₃ and R₄ are each independently —Z—Y, providedthat (1) R₂ and R₄ are not both substituted or unsubstituted aminoradicals; (2) the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in each —Z—Y is 0-3; and (3) the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₁,R₂, R₃ and R₄ is 0-3; each Z is independently a (1) bond; (2) C₁-C₈alkyl or C₂-C₈ alkenyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio,halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 haloradicals; (3) heterocyclyl radical optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl radicals; or (4)aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂ haloalkyl of1-3 halo radicals; each Y is independently a (1) hydrogen radical,provided Z is other than a bond; (2) halo radical; (3) —C(O)—R₂₀,—C(O)—OR₂₁, —C(O)—NR₅R₂₁ or —C(NR₅)—NR₅R₂₁ radical; (4) —OR₂₁,—O—C(O)—R₂₁ or —O—C(O)—NR₅R₂₁ radical; (5) SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀or —S(O)₂—NR₅R₂₁ radical; or (6) —NR₅R₂₁, —NR₂₂—C(O)—R₂₁,—NR₂₂—C(O)—OR₂₀, —NR₂₂—C(O)—NR₅R₂₁, —NR₂₂—C(NR₅)—NR₅R₂₁, —NR₂₂—S(O)₂—R₂₀or —NR₂₂—S(O)₂—NR₅R₂₁ radical; each R₅ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl or C₂-C₅ alkenyl radicals optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio or halo; or (3) phenyl-C₁-C₂-alkyl,heteroaryl-C₁-C₂-alkyl, heterocyclyl-C₁-C₂-alkyl orC₃-C₆-cycloalkyl-C₁-C₂-alkyl radicals optionally substituted by 1-3radicals of amino, di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 halo radicals;each R₂₀ is independently (1) C₁-C₈ alkyl or C₂-C₅ alkenyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃—C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 haloradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl ,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkylor C₁-C₂ haloalkyl of 1-3 halo radicals; each R₂₁ is independentlyhydrogen radical or R₂₀; each R₂₂ is independently (1) hydrogen radical;or (2) C₁-C₄ alkyl radical optionally substituted by a radical of phenylor heteroaryl optionally substituted by 1-3 radicals of amino, di-(C₁-C₂alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂haloalkyl of 1-3 halo radicals; each R₂₃ is independently hydrogen orC₁-C₄ alkyl, or phenyl, heteroaryl, phenyl-C₁-C₂-alkyl orheteroaryl-C₁-C₂-alkyl optionally substituted by 1-3 radicals of amino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl orC₁-C₂ haloalkyl of 1-3 halo radicals; R₁₀ is a hydrogen, R₃₀, —C(O)—R₂₉,—C(O)—NR₃₁R₃₂, —S(O)₂—R₃₀ or —S(O)₂—NR₃₁R₃₂ radical; R₁₁ and R₁₂ areeach independently an aryl or heteroaryl radical optionally substitutedby 1-2 radicals of (1) R₃₀; (2) halo or cyano radicals; (3) —C(O)—R₃₀,—C(O)—OR₂₉, —C(O)—NR₃₁R₃₂ or —C(NR₃₁)—NR₃₁R₃₂ radicals; or (4) —OR₂₉,—SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂, —NR₃₃—C(O)—R₂₉or —NR₃₃—C(O)—OR₃₀ radicals; provided that the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each ofR₁₁ and R₁₂ is 0-1; each R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by (a) amino, C₁-C₄ alkylamino ordi-(C₁-C₄-alkyl)amino radicals; or (b) hydroxy, C₁-C₄ alkoxy,heterocyclyl, phenyl or heteroaryl radicals optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; (2)C₁-C₂ haloalkyl of 1-3 halo radical; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; each R₂₉ is independently hydrogen radical orR₃₀; each R₃₁ is independently hydrogen or C₁-C₄ alkyl radicals; andeach R₃₂ is independently (1) hydrogen radicals; (2) C₁-C₄ alkyl radicaloptionally substituted by phenyl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkyl or trifluoromethyl radicals; or (3) phenyl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkyl ortrifluoromethyl radicals; and each R₃₃ is independently hydrogen ormethyl radical; and wherein heterocyclyl is a radical of a monocyclicsaturated heterocyclic ring system having 5-6 ring members, wherein 1-3ring members are oxygen, sulfur or nitrogen heteroatoms, which isoptionally benzo-fused and optionally substituted by 1-2 oxo or thioxoradicals; aryl is a phenyl or naphthyl radical; and heteroaryl isradical of a monocyclic aromatic heterocyclic ring system having 5-6ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 5. The compound of claim 4 or apharmaceutically acceptable salt thereof, wherein each Z isindependently a (1) bond; (2) C₁-C₄ alkyl or C₂-C₅ alkenyl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy,C₁-C₂ alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₂alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (3) heterocyclyl radical optionallysubstituted by 1-2 radicals of amino, di-(C₁-C₂ alkyl)amino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio or C₁-C₄alkyl radicals; or (4) aryl or heteroaryl radical optionally substitutedby 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; each R₅ isindependently (1) hydrogen radical; (2) C₁-C₄ alkyl radical optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₂-alkyl)amino, hydroxy,C₁-C₂ alkoxy, C₁-C₂ alkylthio or halo; or (3) phenyl-C₁-C₂-alkyl,heteroaryl—C₁-C₂-alkyl, heterocyclyl-C₁-C₂-alkyl orC₃-C₆-cycloalkyl-C₁-C₂-alkyl radicals optionally substituted by 1-3radicals of amino, di-(C₁-C₂-alkyl)amino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, methoxy, methylthio, cyano, C₁-C₄ alkyl or trifluoromethylradicals; each R₂₂ is independently hydrogen or C₁-C₄ alkyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl, or phenyl,heteroaryl, phenyl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; R₁₁ andR₁₂ are each independently an aryl or heteroaryl radical optionallysubstituted by 1-2 radicals of (1) R₃₀; (2) halo or cyano radicals; (3)—C(O)—R₃₀, —C(O)—OR₂₉, —C(O)—NR₃₁R₃₂ or —C(NR₃₁)—NR₃₁R₃₂ radicals; or(4) —OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂radicals; provided that the total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1;each R₃₀ is independently (1) C₁-C₄ alkyl radical optionally substitutedby a phenyl or heteroaryl radical optionally substituted by 1-3 radicalsof amino, di-(C₁-C₂ alkyl)amino, acetamido, hydroxy, C₁-C₂ alkoxy, halo,C₁-C₄ alkyl or trifluoromethyl radicals; (2) trifluoromethyl radical; or(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicalsof amino, di-(C₁-C₂ alkyl)amino, acetamido, hydroxy, C₁-C₂ alkoxy, halo,C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₉ is independentlyhydrogen radical or R₃₀; and each R₃₂ is independently (1) hydrogenradicals; (2) C₁-C₄ alkyl radical or C₁-C₂ alkyl radical substituted byphenyl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, di-(C₁-C₂ alkyl)amino, acetamido, hydroxy, C₁-C₂ alkoxy, C₁-C₄alkyl or trifluoromethyl radicals; or (3) phenyl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,acetamido, hydroxy, C₁-C₂ alkoxy, C₁-C₄ alkyl or trifluoromethylradicals; and wherein heterocyclyl is a radical of a monocyclicsaturated heterocyclic ring system having 5-6 ring members, wherein 1-2ring members are oxygen, sulfur or nitrogen heteroatoms, which isoptionally benzo-fused and optionally substituted by 1-2 oxo or thioxoradicals; aryl is a phenyl or naphthyl radical; and heteroaryl isradical of a monocyclic aromatic heterocyclic ring system having 5-6ring 15 members, wherein 1-2 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally benzo-fused.
 6. The compound of claim 5or a pharmaceutically acceptable salt thereof, wherein each Z isindependently a (1) bond; (2) C₁-C₄ alkyl or C₂-C₅ alkenyl radicaloptionally substituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,halo, or aryl or heteroaryl optionally substituted by 1-2 radicals Ofamino, di-(C₁-C₂ alkyl)amino, acetamido, (C₁-C₄ alkoxy)carbonylamino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; or (3) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, di-(C₁-C₂ alkyl)amino, acetamido,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; each Y isindependently a (1) hydrogen radical, provided Z is other than a bond;(2) halo radical; (3) —C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4)—OR₂₁, —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5)—NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—C(O)—OR₂₀, —NR₂₂—C(O)—NR₅R₂₁,—NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; each R₅ is independently(1) hydrogen radical; (2) C₁-C₄ alkyl radical optionally substituted by1-3 halo radicals; or (3) phenyl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl,radicals optionally substituted by 1-3 radicals of amino, dimethylamino,hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; eachR₂₀ is independently (1) C₁-C₈ alkyl or C₂-C₅ alkenyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or C₁-C₂ haloalkyl of 1-3 haloradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, (C₁-C₄ alkoxy)carbonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, acetamido, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkylor trifluoromethyl radicals; each R₂₁ is independently hydrogen radicalor R₂₀; each R₂₃ is independently hydrogen or C₁-C₄ alkyl, orphenyl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl optionally substituted by1-3 radicals of amino, di-(C₁-C₂ alkyl)amino, acetamido, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano,halo, C₁-C₄ alkyl or trifluoromethyl radicals; R₁₁ and R₁₂ are eachindependently an aryl or heteroaryl radical optionally substituted by1-2 radicals of (1) R₃₀; (2) halo or cyano radicals; or (3)—C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂,—NR₃₁R₃₂ or —NR₃₃—C(O)—R29 radicals; provided that the total number ofaryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted oneach of R₁₁ and R₁₂ is 0-1; each R₃₀ is independently (1) C₁-C₄ alkylradical optionally substituted by a phenyl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;(2) trifluoromethyl radical; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-3 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;each R₂₉ is independently hydrogen radical or R₃₀; each R₃₁ isindependently hydrogen, methyl or ethyl radicals; and each R₃₂ isindependently (1) hydrogen radicals; (2) C₁-C₄ alkyl radical or C₁-C₂alkyl radical substituted by phenyl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy,methoxy, methyl or trifluoromethyl radicals; or (3) phenyl or heteroarylradical optionally substituted by 1-3 radicals of amino, dimethylamino,acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals.
 7. Thecompound of claim 6 or a pharmaceutically acceptable salt thereof,wherein X₁ is N; X₂ is CH or CR₂; X₃ is CH or CR₃; and X₄ is CH or CR₄;wherein R₂, R₃ and R4 are each independently —Z—Y, provided that (1) R₂and R₄ are not both substituted or unsubstituted amino radicals; (2) thetotal number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicalsin each —Z—Y is 0-3; and (3) the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂, R₃ and R₄ is0-3.
 8. The compound of claim 7 or a pharmaceutically acceptable saltthereof, wherein R₃ is halo, trifluoromethyl, phenyl, methyl,hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy,—C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁radicals; and R₂ and R₄ are each independently —Z—Y, provided that (1)R₂ and R₄ are not both substituted or unsubstituted amino radicals; (2)the total number of aryl, heteroaryl, cycloalkyl and heterocyclylradicals in each —Z—Y is 0-3; and (3) the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂, R₃ and R₄ is0-3.
 9. The compound of claim 8 or a pharmaceutically acceptable saltthereof, wherein X₁ is N; X₂ is CR₂; X₃ is CH or CR₃; and X₄ is CH; andwherein R₂ is —Z—Y, provided that the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂ is 0-3; R₃ ishalo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; R₁₁ is a heteroaryl radical optionallysubstituted by 1-2 radicals of (1) R₃₀; (2) halo or cyano radicals; or(3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;and R₁₂ is an aryl radical optionally substituted by 1-2 radicals of (1)R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁ R₃₂, —OR₂₉, —SR₂₉,—S(O)—R₃₀, —S(O)₂—R₃₀, —S(O)₂—NR₃₁ R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉radicals; provided that the total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1. 10.The compound of claim 9 or a pharmaceutically acceptable salt thereof,wherein Z is independently a (1) bond; or (2) C₁-C₄ alkyl radicaloptionally substituted by 1-2 radicals of amino, di-(C₁-C₂ alkyl)amino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,halo, or aryl or heteroaryl optionally substituted by 1-2 radicals ofhydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; each R₅ is independently hydrogen or C₁-C₄alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C5 alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionally substituted by1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀,—C(O)—R₂₉ or —C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by a phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethylradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy,methyl or trifluoromethyl radicals; R₂₉ is an aryl or heteroarylradicals optionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;R₃₁ is independently hydrogen, methyl or ethyl radicals; and R₃₂ isindependently (1) hydrogen or C₁-C₄ alkyl radical; or (2) phenyl orheteroaryl radical optionally substituted by 1-2 radicals of amino,dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethylradicals.
 11. The compound of claim 10 or a pharmaceutically acceptablesalt thereof, wherein Z is independently a (1) bond; or (2) C₁-C₄ alkylradical optionally substituted by 1-2 radicals of amino,t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio orhalo radicals; Y is independently a (1) hydrogen radical, provided Z isother than a bond; (2) halo radical; (3) —C(O)—R₂₀, —C(O)—OR₂₁ or—C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁, —S(O)—R₂₀, —S(O)₂—R₂₀ or—S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is a hydrogen radical; each R₂₀ isindependently (1) C₁-C₆ alkyl radicals optionally substituted by 1-3radicals of —CO₂R₂₃, amino, methylamino, dimethylamino,t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-(methyl)amino,aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio,methylsulfinyl, methylsulfonyl, halo or C₅-C₆ cycloalkyl, heterocyclyl,phenyl or heteroaryl radicals optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo,methyl or trifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo,azido, methyl or trifluoromethyl radicals; each R₂₁ is independentlyhydrogen radical or R₂₀; each R₂₂ is independently hydrogen or methylradical; each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀is a hydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 12. The compound of claim 11 or apharmaceutically acceptable salt thereof, wherein R₂ is independently Y,provided that the combined total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R₂ is 0-3; R₃ is halo, trifluoromethyl,phenyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, trifluoromethoxy,acetyl, methoxycarbonyl, ethoxycarbonyl, amido or N,N-dimethylamidoradicals; and Y is independently a (1) halo radical; (2) —C(O)—R₂₀ or—C(O)—NR₅R₂₁ radical; (3) —OR₂₁, —SR₂₁ or —S(O)—R₂₀ radical; or (4)—NR₅R₂₁, —NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical.13. The compound of claim 12 or a pharmaceutically acceptable saltthereof, wherein R₃ is halo or trifluoromethyl radicals; Y isindependently a halo, —NR₅R₂₁, —NR₂₂—C(O)—R₂₁ or —NR₂₂—S(O)₂—R₂₀radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicals optionallysubstituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted byt-butoxycarbonyl; or (3) aryl or heteroaryl radicals optionallysubstituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, methoxy, halo,azido, methyl or trifluoromethyl radicals; each R₂₁ is independentlyhydrogen radical or R₂₀; R₁₁ is a 4-pyridyl radical optionallysubstituted by a radical of amino, dimethylamino, acetamido, hydroxy,halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R₁₂ is anunsubstituted phenyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals.14. The compound of claim 6 or a pharmaceutically acceptable saltthereof, wherein X₁ is N; X₂ is CH or CR₂; X₃ is CH or CR₃; and X₄ is N;wherein R₂ and R₃ are each independently —Z—Y, provided that (1) thetotal number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicalsin each —Z—Y, is 0-3; and (2) the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂ and R₃ is 0-3.15. The compound of claim 14 or a pharmaceutically acceptable saltthereof, wherein R₃ is halo, trifluoromethyl, phenyl, methyl,hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy,—C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁radicals; R₂ is —Z—Y, provided that (1) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y, is 0-3;and (2) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ and R₃ is 0-3; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of (1) R₃₀; (2) halo or cyanoradicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉radicals; and R₁₂ is an aryl radical optionally substituted by 1-2radicals of (1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀—S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or—NR₃₃—C(O)—R₂₉ radicals; provided that the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each ofR₁₁ and R₁₂ is 0-1.
 16. The compound of claim 15 or a pharmaceuticallyacceptable salt thereof, wherein X₁ is N; X₂ is CR₂; X₃ is CH or CR₃;and X₄ is N; and wherein R₂ is —Z—Y, provided that the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₂is 0-3; R₃ is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl,hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl,methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido,methylsulfonyl or aminosulfonyl radicals; Z is independently a (1) bond;or (2) C₁-C₄ alkyl radical optionally substituted by 1-2 radicals ofamino, di-(C₁-C₂ alkyl)amino, (C₁-C₄ alkoxy)carbonylamino, hydroxy,C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, or aryl or heteroaryl optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; each R₅ isindependently hydrogen or C₁-C₄ alkyl radical; each R₂₀ is independently(1) C₁-C₈ alkyl radicals optionally substituted by 1-3 radicals of—CO₂R₂₃, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N—((C₁-C₄alkoxy)carbonyl)-N—(C₁-C₄ alkyl)amino, aminocarbonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,halo or C₃-C₆ cycloalkyl, heterocyclyl, aryl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, di-(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; (2)heterocyclyl radical optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl;or (3) aryl or heteroaryl radicals optionally substituted by 1-2radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, azido, C₁-C₄ alkyl or trifluoromethyl radicals;each R₂₁ is independently hydrogen radical or R₂₀; each R₂₃ isindependently hydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,cyano, halo, C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen,R₃₀, —C(O)—R₂₉ or —C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₂₉ is an aryl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 17. The compound of claim 16 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 18. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein X₁ is N; X₂ is CH orCR₂; X₃ is N; and X₄ is CH or CR₄; wherein R₂ and R₄ are eachindependently —Z—Y, provided that (1) R₂ and R₄ are not both substitutedor unsubstituted amino radicals; (2) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (3) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ and R₄ is 0-3.
 19. The compound of claim 18or a pharmaceutically acceptable salt thereof, wherein R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; R₂ is —Z—Y, providedthat (1) R₂ and R₄ are not both substituted or unsubstituted aminoradicals; (2) the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in each —Z—Y is 0-3; and (3) the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₂and R₄ is 0-3; R₁₁ is a heteroaryl radical optionally substituted by 1-2radicals of (1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an arylradical optionally substituted by 1-2 radicals of (1) R₃₀; (2) halo orcyano radicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀,—S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1.
 20. Thecompound of claim 19 or a pharmaceutically acceptable salt thereof,wherein X₁ is N; X₂ is CR₂; X₃ is N; and X₄ is CH or CR₄; wherein R₂ is—Z—Y, provided that (1) R₂ and R₄ are not both substituted orunsubstituted amino radicals; and (2) the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂ is 0-3; R₄ ishalo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; Z is independently a (1) bond; or (2) C₁-C₄alkyl radical optionally substituted by 1-2 radicals of amino, di-(C₁-C₂alkyl)amino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄alkyl or trifluoromethyl radicals; each R₅ is independently hydrogen orC₁-C₄ alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N—((C₁-C₄ alkoxy)carbonyl)-N—(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionally substituted by1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀,—C(O)—R₂₉ or —C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by a phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethylradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy,methyl or trifluoromethyl radicals; R₂₉ is an aryl or heteroarylradicals optionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 21. The compound of claim 20 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 22. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein X₁ is N; X₂ is N; X₃is CH or CR₃; and X₄ is CH or CR₄; wherein R₃ and R₄ are eachindependently —Z—Y, provided that (1) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (2) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ and R₄ is 0-3.
 23. The compound of claim 22or a pharmaceutically acceptable salt thereof, wherein R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; R₃ is —Z—Y, providedthat (1) the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in each —Z—Y is 0-3; and (2) the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₃and R₄ is 0-3; R₁₁ is a heteroaryl radical optionally substituted by 1-2radicals of (1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an arylradical optionally substituted by 1-2 radicals of (1) R₃₀; (2) halo orcyano radicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀,—S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1.
 24. Thecompound of claim 23 or a pharmaceutically acceptable salt thereof,wherein X₁ is N; X₂ is N; X₃ is CR₃; and X₄ is CH or CR₄; wherein R₃ is—Z—Y, provided that the combined total number of aryl, heteroaryl,cycloalkyl and heterocyclyl radicals in R₃ is 0-3; R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; Z is independently a (1) bond; or (2) C₁-C₄alkyl radical optionally substituted by 1-2 radicals of amino, di-(C₁-C₂alkyl)amino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄alkyl or trifluoromethyl radicals; each R₅ is independently hydrogen orC₁-C₄ alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N—((C₁-C₄ alkoxy)carbonyl)-N—(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkyl or C₁-C₄ alkyl; or (3) aryl or heteroaryl radicalsoptionally substituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkylor trifluoromethyl radicals; each R₂₁ is independently hydrogen radicalor R₂₀; each R₂₃ is independently hydrogen or C₁-C₄ alkyl, orphenyl-C₁-C₂-alkyl optionally substituted by 1-2 radicals of hydroxy,C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀, —C(O)—R₂₉ or—C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, cyano, methoxy, methyl or trifluoromethyl radicals; R₁₂ is an arylradical optionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl,methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; R₃₀is independently (1) C₁-C₄ alkyl radical optionally substituted by aphenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl ortrifluoromethyl radicals; (2) trifluoromethyl radical; or (3) aryl orheteroaryl radicals optionally substituted by 1-3 radicals of amino,dimethylamino, acetamido, hydroxy, halo, methoxy, methyl ortrifluoromethyl radicals; R₂₉ is an aryl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 25. The compound of claim 24 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 26. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein X₁ is CH or CR₁; X₂ isCH or CR₂; X₃ is N; and X₄ is N; wherein R₁ and R₂ are eachindependently —Z—Y, provided that (1) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (2) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₁ and R₂ is 0-3.
 27. The compound of claim 26or a pharmaceutically acceptable salt thereof, wherein R₁ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; R₂ is —Z—Y, providedthat (1) the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in each —Z—Y is 0-3; and (2) the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₁and R₂ is 0-3; R₁₁ is a heteroaryl radical optionally substituted by 1-2radicals of (1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an arylradical optionally substituted by 1-2 radicals of (1) R₃₀; (2) halo orcyano radicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀,—S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1.
 28. Thecompound of claim 27 or a pharmaceutically acceptable salt thereof,wherein X₁ is CH or CR₁; X₂ is CR₂; X₃ is N; and X₄ is N; wherein R₁ ishalo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; R₂ is —Z—Y, provided that the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₂is 0-3; Z is independently a (1) bond; or (2) C₁-C₄ alkyl radicaloptionally substituted by 1-2 radicals of amino, di-(C₁-C₂ alkyl)amino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio,halo, or aryl or heteroaryl optionally substituted by 1-2 radicals ofhydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; each R₅ is independently hydrogen or C₁-C₄alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N—((C₁-C₄ alkoxy)carbonyl)-N—(C ₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionally substituted by1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀,—C(O)—R₂₉ or —C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₂₉ is an aryl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 29. The compound of claim 28 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 30. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein X₁ is CH or CR₁; X₂ isCH or CR₂; X₃ is CH or CR₃; and X₄ is CH or CR₄; provided that at leastone of X₁, X₂, X₃ and X₄ is CH; wherein R₁, R₂, R₃ and R₄ are eachindependently —Z—Y, provided that (1) R₂ and R₄ are not both substitutedor unsubstituted amino radicals; (2) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (3) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₁, R₂, R₃ and R₄ is ₀-3.
 31. The compound ofclaim 30 or a pharmaceutically acceptable salt thereof, wherein X₁ isCH; X₂ is CH; X₃ is CH or CR₃; and X₄ is CH or CR₄; wherein R₃ and R₄are each independently —Z—Y, provided that (1) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (2) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ and R₄ is 0-3.
 32. The compound of claim 31or a pharmaceutically acceptable salt thereof, wherein R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁,—C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; wherein R₃ is —Z—Y,provided that (1) the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in each —Z—Y is 0-3; and (2) the combined totalnumber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R₃and R₄ is 0-3; R₁₁ is a heteroaryl radical optionally substituted by 1-2radicals of (1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂,—OR₂₉, —SR₂₉, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an arylradical optionally substituted by 1-2 radicals of (1) R₃₀; (2) halo orcyano radicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀,—S(O)₂—R₃₀, —S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals;provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals substituted on each of R₁₁ and R₁₂ is 0-1.
 33. Thecompound of claim 32 or a pharmaceutically acceptable salt thereof,wherein X₁ is CH; X₂ is CH; X₃ is CR₃; and X₄ is CH or CR₄; wherein R₃is —Z—Y, provided that the combined total number of aryl, heteroaryl,cycloalkyl and heterocyclyl radicals in R₃ is 0-3; R₄ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl,ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl oraminosulfonyl radicals; Z is independently a (1) bond; or (2) C₁-C₄alkyl radical optionally substituted by 1-2 radicals of amino, di-(C₁-C₂alkyl)amino, (C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄alkyl or trifluoromethyl radicals; each R₅ is independently hydrogen orC₁-C₄ alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N—((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionally substituted by1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀,—C(O)—R₂₉ or —C(O)—NR₃₁ R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by a phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethylradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy,methyl or trifluoromethyl radicals; R₂₉ is an aryl or heteroarylradicals optionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 34. The compound of claim 33 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t-butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 35. The compound of claim 30 or apharmaceutically acceptable salt thereof, wherein X₁ is CH; X₂ is CH orCR₂; X₃ is CH or CR₃; and X₄ is CH; wherein R₂ and R₃ are eachindependently —Z—Y, provided that (1) the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in each —Z—Y is 0-3;and (2) the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ and R₃ is 0-3.
 36. The compound of claim 35or a pharmaceutically acceptable salt thereof, wherein R₃ is halo,trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl,dimethylamino, methoxy, trifluoromethoxy, —C(O)—R₂₀, —C(O)—OR₂₁, —C(O)—NR₅R₂₁, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁ radicals; R₂ is —Z—Y, provided that(1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclylradicals in each —Z—Y is 0-3; and (2) the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R₂ and R₃ is 0-3;R₁₁ is a heteroaryl radical optionally substituted by 1-2 radicals of(1) R₃₀; (2) halo or cyano radicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉,—NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; and R₁₂ is an aryl radicaloptionally substituted by 1-2 radicals of (1) R₃₀; (2) halo or cyanoradicals; or (3) —C(O)—NR₃₁R₃₂, —OR₂₉, —SR₂₉, —S(O)—R₃₀, —S(O)₂—R₃₀,—S(O)₂—NR₃₁R₃₂, —NR₃₁R₃₂ or —NR₃₃—C(O)—R₂₉ radicals; provided that thetotal number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicalssubstituted on each of R₁₁ and R₁₂ is 0-1.
 37. The compound of claim 36or a pharmaceutically acceptable salt thereof, wherein X₁ is CH; X₂ isCR₂; X₃ is CH or CR₃; and X₄ is CH; and wherein R₂ is —Z—Y, providedthat the combined total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R₂ is 0-3; R₃ is halo, trifluoromethyl, phenyl,methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy,trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido,N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; Z isindependently a (1) bond; or (2) C₁-C₄ alkyl radical optionallysubstituted by 1-2 radicals of amino, di-(C₁-C₂ alkyl)amino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, oraryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy,C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; each R₅ is independently hydrogen or C₁-C₄alkyl radical; each R₂₀ is independently (1) C₁-C₈ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, halo or C₃-C₆ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl ortrifluoromethyl radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,azido, C₁-C₄ alkyl or trifluoromethyl radicals; each R₂₁ isindependently hydrogen radical or R₂₀; each R₂₃ is independentlyhydrogen or C₁-C₄ alkyl, or phenyl-C₁-C₂-alkyl optionally substituted by1-2 radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, cyano, halo,C₁-C₄ alkyl or trifluoromethyl radicals; R₁₀ is a hydrogen, R₃₀,—C(O)—R₂₉ or —C(O)—NR₃₁R₃₂ radical; R₁₁ is a heteroaryl radicaloptionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethylradicals; R₁₂ is an aryl radical optionally substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl ortrifluoromethyl radicals; R₃₀ is independently (1) C₁-C₄ alkyl radicaloptionally substituted by a phenyl or heteroaryl radical optionallysubstituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy,halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethylradical; or (3) aryl or heteroaryl radicals optionally substituted by1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy,methyl or trifluoromethyl radicals; R₂₉ is an aryl or heteroarylradicals optionally substituted by 1-2 radicals of amino, dimethylamino,acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;and R₃₂ is independently (1) hydrogen or C₁-C₄ alkyl radical; or (2)phenyl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, dimethylamino, acetamido, hydroxy, methoxy, methyl ortrifluoromethyl radicals.
 38. The compound of claim 37 or apharmaceutically acceptable salt thereof, wherein Z is independently a(1) bond; or (2) C₁-C₄ alkyl radical optionally substituted by 1-2radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy,methoxy, methylthio or halo radicals; Y is independently a (1) hydrogenradical, provided Z is other than a bond; (2) halo radical; (3)—C(O)—R₂₀, —C(O)—OR₂₁ or —C(O)—NR₅R₂₁ radical; (4) —OR₂₁, —SR₂₁,—S(O)—R₂₀, —S(O)₂—R₂₀ or —S(O)₂—NR₅R₂₁radical; or (5) —NR₅R₂₁,—NR₂₂—C(O)—R₂₁, —NR₂₂—S(O)₂—R₂₀ or —NR₂₂—S(O)₂—NR₅R₂₁ radical; R₅ is ahydrogen radical; each R₂₀ is independently (1) C₁-C₆ alkyl radicalsoptionally substituted by 1-3 radicals of —CO₂R₂₃, amino, methylamino,dimethylamino, t—butoxycarbonylamino,N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy,butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl,halo or C₅-C₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, dimethylamino,acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethylradicals; (2) heterocyclyl radical optionally substituted by 1-2radicals of t-butoxycarbonyl, hydroxy, or C₁-C₄ alkyl; or (3) aryl orheteroaryl radicals optionally substituted by 1-2 radicals oft-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido,methyl or trifluoromethyl radicals; each R₂₁ is independently hydrogenradical or R₂₀; each R₂₂ is independently hydrogen or methyl radical;each R₂₃ is independently hydrogen or C₁-C₄ alkyl radicals; R₁₀ is ahydrogen or methyl radical; R₁₁ is a 4-pyridyl, 4-quinolinyl,4-imidazolyl or 4-pyrimidinyl radical optionally substituted by aradical of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methyl or trifluoromethyl radicals; and R₁₂ is an unsubstitutedphenyl or naphthyl radical or a phenyl radical substituted by 1-2radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano,methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl,methyl or trifluoromethyl radicals.
 39. The compound of claim 1 whichis: 3-(4-pyridyl)-2-(4-fluorophenyl)indole;3-(4-fluorophenyl)-2-(4-pyridyl)indole;6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-amino-3-(4-fluorophenyl)-2-(4-pyridyl)-7-aza-indole;6-(4′-t-butoxycarbonylamino-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-amino-1′-oxo-butylamino)-3-(4pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-ureido-1′1-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-ureido-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(6′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(6′-amino-1′-oxo-2′-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-t-butoxycarbonylamino-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-amino-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(4-iodophenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(4-iodophenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-methyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-methyl-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′,4′-dimethyl-1′-oxo-2′-t-butoxycarbonylaminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′,4′-dimethyl-1′-oxo-2′-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-t-butoxycarbonylamino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(5′-amino-1′-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(6′-t-butoxycarbonylamino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(6′-amino-1′-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-cyclohexyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-cyclohexyl-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-t-butoxycarbonyl-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-carboxy-1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-O-t-butoxy-1′-oxo-2′-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-hydroxy1′-oxo-2′-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenyl-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenyl-140-oxo-2′-D,L-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(4-t-butoxyphenyl)-1′-oxo-2′-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(4-hydroxyphenyl)-1′-oxo-2′-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-t-butoxycarbonylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;b6-(2′-amino--1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(methylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-137-aza-indole;6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(phenylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-N-phthaloyl-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-N-phthaloyl-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole;6-(2′-N-t-butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2S′-dimethylamino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-dimethylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-N-methyl-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-N-methyl-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-N-t-butoxycarbonylisonipecotylamino)3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-methylsulfoxo-1′-oxo-2′S-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-methylsulfoxo-1′-oxo-2′S-aminobutylamino)-13-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(3-pyridyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(3-pyridyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(N,N-Di-t-butoxycarbonyl-L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-1indole;6-(N-t-butoxycarbonyl-3(S) 1′, 2′, 3′,4′-tetrahydro-3′-isoquinolinyloxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3(S)1′,2′,3′,4′-tetrahydro-3′-isoquinolinyloxoamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′R—N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′R-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′S-N-t-butoxycarbonylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′R-N-t-butoxycarbonyl-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-phenyl-1′-oxo-2′R-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenyl-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S-t-butoxycarbonyl-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S—N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S-t-butoxycarbonyl-N-methyl--4-methyl-2-aminopentyl-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′S-N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′R-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(1′-oxo-2′R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(2-thienyl)-1′-oxo-2′-(L)-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(2-thienyl)-1′-oxo-2′-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(4-azidophenyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(3-benzothienyl)-1′-oxo-2′S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-(3-benzothienyl)-1′-oxo-2′S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-phenyl-1′-oxo-2′-(L)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-phenyl-1′-oxo-2′-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-phenyl--1′-oxo-2′-(D)-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(4′-phenyl-1-oxo-2-(D)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole;6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-Amino-5-chloro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(di-isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′,2′-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-thienylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′,3′di-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(3′-phenyl-1′-oxo-2′-(R,S)-methylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;6-(3′,3′-dimethyl-1′-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(ethoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;6-(2′S-amino-1-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole;or6-(2′S-amino-1′-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-cyclohexylmethyl-7-aza-indole.40. A pharmaceutical composition comprising a compound of claims 1 to 39and a pharmaceutically acceptable carrier.
 41. A method of prophylaxisor treatment of inflammation comprising administering an effectiveamount of a compound of claims 1 to
 39. 42. A method of prophylaxis ortreatment of inflammation comprising administering an effective amountof a composition of claim
 40. 43. A method of prophylaxis or treatmentof rheumatoid arthritis, Pagets disease, osteophorosis, multiplemyeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic βcell destruction, osteoarthritis, rheumatoid spondylitis, goutyarthritis, inflammatory bowel disease, adult respiratory distresssyndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis,ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscledegeneration, cachexia, Reiter's syndrome, type I diabetes, type IIdiabetes, bone resorption diseases, graft vs. host reaction, Alzheimer'sdisease, stroke, myocardial infarction, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria,sepsis, septic shock, toxic shock syndrome, fever or myalgias due toinfection, or infections of HIV-1, HIV-2, HIV-3, cytomegalovirus,influenza, adenovirus, herpes viruses or herpes zoster in a mammalcomprising administering an effective amount of a compound of claims1-39.
 44. A method of prophylaxis or treatment of rheumatoid arthritis,Pagets disease, osteophorosis, multiple myeloma, uveititis, acute orchronic myelogenous leukemia, pancreatic β cell destruction,osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatorybowel disease, adult respiratory distress syndrome (ARDS), psoriasis,Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis,contact dermatitis, asthma, muscle degeneration, cachexia, Reiter'ssyndrome, type I diabetes, type II diabetes, bone resorption diseases,graft vs. host reaction, Alzheimer's disease, stroke, myocardialinfarction, ischemia reperfusion injury, atherosclerosis, brain trauma,multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shocksyndrome, fever or myalgias due to infection, or infections of HIV-1,HIV-2, HIV-3, cytomegalovirus, influenza, adenovirus, herpes viruses orherpes zoster in a mammal comprising administering an effective amountof a composition of claim
 40. 45. A method of lowering plasmaconcentrations of either or both TNF-a and IL-1 comprising administeringan effective amount of a compound of claims 1-39.
 46. A method oflowering plasma concentrations of either or both TNF-a and IL-1comprising administering an effective amount of a composition of claim40.
 47. A method of lowering plasma concentrations of either or bothIL-6 and IL-8 comprising administering an effective amount of a compoundof claims 1-39.
 48. A method of lowering plasma concentrations of eitheror both IL-6 and IL-8 comprising administering an effective amount of acomposition of claim
 40. 49. A method of prophylaxis or treatment ofdiabetes disease in a mammal comprising administering an effectiveamount of a compound according to claims 1 to 39 to produce a glucagonantagonist effect.
 50. A method of prophylaxis or treatment of diabetesdisease in a mammal comprising administering an effective amount of apharmaceutical composition according to claim 40 to produce a glucagonantagonist effect.
 51. A method of prophylaxis or treatment of a paindisorder in a mammal comprising administering an effective amount of acompound according to claims 1 to
 39. 52. A method of prophylaxis ortreatment of a pain disorder in a mammal comprising administering aneffective amount of a pharmaceutical composition according to claim 40.53. A method of decreasing prostaglandins production in a mammalcomprising administering an effective amount of a compound according toclaims 1 to
 39. 54. A method of decreasing prostaglandins production ina mammal comprising administering an effective amount of apharmaceutical composition according to claim
 40. 55. A method ofdecreasing cyclooxygenase enzyme activity in a mammal comprisingadministering an effective amount of a compound according to claims 1 to39.
 56. The method of claim 55 wherein the cyclooxygenase enzyme isCOX-2.
 57. A method of decreasing cyclooxygenase enzyme activity in amammal comprising administering an effective amount of a pharmaceuticalcomposition according to claim
 40. 58. The method of claim 57 whereinthe cyclooxygenase enzyme is COX-2.